Clinical Trials Register

Summary
EudraCT Number:	2019-001542-17
Sponsor's Protocol Code Number:	T109/2019Xe-SAH
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-07-08
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

Finland - Fimea

A.2

EudraCT number

2019-001542-17

A.3

Full title of the trial

Effect of xenon on brain injury, neurological outcome and survival in patients after aneurysmal subarachnoid hemorrhage

Ksenonin vaikutus lukinkalvonalainen verenvuoto -potilaiden aivovaurioon, neurologiseen toipumiseen ja kuolleisuuteen

A.3.1

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

Effect of xenon on brain injury, neurological outcome and survival in patients after aneurysmal subarachnoid hemorrhage

Ksenonin vaikutus lukinkalvonalainen verenvuoto -potilaiden aivovaurioon, neurologiseen toipumiseen ja kuolleisuuteen

A.3.2

Name or abbreviated title of the trial where available

Xe-SAH

Xe-SAV

A.4.1

Sponsor's protocol code number

T109/2019Xe-SAH

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	Timo Laitio
B.1.3.4	Country	Finland
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	Academy of Finland
B.4.2	Country	Finland
B.4.1	Name of organisation providing support	State Research Funding
B.4.2	Country	Finland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Timo Laitio
B.5.2	Functional name of contact point	Turku University Hospital
B.5.3	Address:
B.5.3.1	Street Address	Hämeentie 11
B.5.3.2	Town/ city	Turku
B.5.3.3	Post code	20521
B.5.3.4	Country	Finland
B.5.4	Telephone number	+358504653201
B.5.6	E-mail	timo.laitio@elisanet.fi

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	Xenon pro Anesthesia
D.2.1.1.2	Name of the Marketing Authorisation holder	AIR LIQUIDE Medical GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Xenon pro Anesthesia
D.3.4	Pharmaceutical form	Medicinal gas, liquefied
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
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)	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	Yes
D.3.11.13.1	Other medicinal product type	Noble gas xenon, medicinal gas
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Conoxia (Air/Oxygen with at least 21% oxygen)
D.2.1.1.2	Name of the Marketing Authorisation holder	Linde GAS
D.2.1.2	Country which granted the Marketing Authorisation	Finland
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	Conoxia
D.3.4	Pharmaceutical form	Medicinal gas, cryogenic
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
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)	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	Yes
D.3.11.13.1	Other medicinal product type	Medicinal gas

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

Acute rupture of cerebral aneurysm, subarachnoid hemorrhage (SAH), unconsciousness, brain injury.

Aivavaltimon aneyrysman repeämän aiheuttama lukinkalvonalainen -verenvuoto, tajuttomuss, aivovaurio

E.1.1.1

Medical condition in easily understood language

Acute rupture of brain aneurysm, unconciousness and need for ventilatory support in the intensive care unit. Mortality is 50% and 25% will survive without neurological or psychological problems.

Aivojen verisuonipullistuman repeämän aiheuttama aivoverenvuoto, tajuttomuss, tarve hengityskonehoidolle teho-osastolla. Kuolleisuus 50% ja 25% selviää oireettomaksi.

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	10008078
E.1.2	Term	Cerebral arterial aneurysm
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

Main Objective:
To explore neuroprotective properties of xenon in patients after aneurysmal subarachnoid hemorrhage (SAH).
Primary endpoint: Global fractional anisotropy of white matter of diffusion tensor imaging (DTI). Hypothesis: White matter damage is less severe in xenon treated patients, i.e. global fractional anisotropy is significantly higher in the xenon group than in the control group as assessed with the 1st MRI within 48-96 hours after onset of SAH symptoms.

Tutkimuksen päätavoite:
Selvittää ksenonin aivoja suojaavat ominaisuudet lukinkalvonalainen -verenvuotopotilailla
Primaari päätetapahtuma: Valkean aineen vaurio on vähäisempi ksenonilla hoidetuilla potilailla, eli aivojen valkean aineen magneettikuvauksella 48-96 tuntia oireiden alusta saatu globaali fraktioitu anisotropia arvo on merkittävästi korkeampi ksenonpotilailla.

E.2.2

Secondary objectives of the trial

Fractional anisotropy of white matter at cerebellum and/or at corpus callosum. Exploratory endpoints: 1. Composite of radiological EBI (i.e. the 1st MRI) and DCI (Criterion of DCI: 1. a new focal neurological deficit/decrease in level of consciousness not due to other causes, e.g. hydrocephalus, seizures, metabolic derangement, infection, sedation, 2. a new infarct on follow-up imaging after 4 days post-SAH, i.e. 2nd MRI, or 3. both 1 and 2), and poor outcome (good: mRS 0-2; poor: mRS 3-6) at 3-months and at 1 year. 3. Neurogenic Stress Cardiomyopathy and Stunned Myocardium. 4 Need for ICP therapies (hypothermia, decompressive craniotomy); 8. Development of prognostication models for EBI and DCI and long-term outcome at 1 and 2 years after SAH by combining data of brain imaging, clinical data (including Turku Aneurysm Data) and metabolomics; 11. Activity of microglia cells

Pikkuaivojen ja corpus callosumin valkean aineen fraktioitu anisotropia
Eksploratiiviset päätetaphtumat: 1. Radiologisesti havaittava varhainen aivovaurio ja/tai myöhäinen aivojen hapenpuute (DCI) (DCI kriteerit: 1. uusi paikallinen neurologinen puutosoire/tajunnan tason lasku ilman muuta syytä esimerkiksi hydrocephalus, kouristelu, metabolinen häiriö, infektio, sedaatio, 2. uusi infarkti seurannan aikana 4 päivää tai myöhemmin vuodon jälkeen, tai 3. 1 ja 2, ja huono neurologinen lopputulema (hyvä: mRS 0-2; huono: mRS 3-6) 3 kk ja vuoden kuluttua vuodosta)
2. Neurogenic Stress Cardiomyopathy and Stunned Myocardium
3. Luodaan ennusteellisia malleja aikaiselle aivovauriolle (EBI), myöhäiselle aivojen hapenpuutteelle (DCI) ja pitkäaikaiselle selviämiselle 3 kuukauden, 1 vuoden ja 2 vuoden kuluttua SAV oireiden alusta. Tutkimusta tehdään yhdistämällä: i) aivokuvantaminen, ii) kliininen informaatio, iii) plasman ja likvorin metabolomiikka

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Aneurysmal subarachnoid hemorrhage visible on CTA or DSA.
2. Hunt-Hess 3-5
3. Age of ≥ 18 years
4. Intubated.
5. GCS 3–12 obtained off neuromuscular blocking agents
6. Xenon treatment started within 6 hours after onset of SAH symptoms

1. Aneurysmaattinen lukinkalvonalinen verenvuoto
2. Hunt-Hess 3-5
3. Ikä 18 - 70 vuotta
4. Intuboitu ja ventilaattorihoidon tarpeessa.
5. GCS 3–12 ilman lihasrelaksaatiota
6. Ksenonhoidon aloitus 6 tunnin kuluessa SAV oireiden alusta

E.4

Principal exclusion criteria

1. Acute traumatic brain injury
2. Maximum diameter of intracerebral hemorrhage > 2.5 cm
3. Pneumothorax or pneumomediastinum,
4. Acute lung injury requiring ≥ 60% FIO2 (fraction of inspired oxygen).
5. Systolic arterial pressure < 80 mmHg or mean arterial pressure < 60 mmHg for over 30 min period
6. Bilaterally fixed and dilated pupils
7. Positive pregnancy test, known pregnancy, or current breast-feeding
8. Chronic neurological deficiency due to chronic traumatic brain injury or other neurological illness
9. Imminent death or current life-threatening disease
10. Current enrollment in another interventional study
11. The subject is known to have a clinically significant laboratory abnormality, medical condition (such as decompensated liver disease or severe chronic obstructive pulmonary disease), or social circumstance that, in the investigator’s opinion, makes it inappropriate for the subject to participate in this clinical trial.
12. Presence of implants or foreign bodies which are not known to be MRI safe

1. Akuutti traumaattinen aivovaurio
2. Aivokudoksen sisäinen verenvuoto > 2.5 cm
3. Pneumothorax tai pneumomediastinum
4. Akuutti keuhkovaurio vaatien ≥ 60% FIO2.
5. Systolinen verenpaine < 80 mmHg tai keskiverenpaine < 60 mmHg yli 30 minuutin ajan
6. Bilateraalisesti laajentuneet pupillit ilman valoreaktiota
7. Positiivinen raskaustesti, raskaana tai imettää
8. Krooninen neurologinen puutosoireisto esimerkiksi aiemman traumaattisen, iskeemisen aivovaurion tai muun neurologisen sairauden seurauksena
9. Henkeäuhkaava sairaus tai kuolemaisillaan muuhun sairauteen
10. Osallistuminen toiseen lääketutkimukseen
11. Muut kliinisesti merkittävät epänormaalit laboratorioarvot, sairaus (esim inkomensoitu maksasairaus, vaikea COPD), tai sosiaalinen tilanne, jotka tekevät tutkijan mielestä potilaan osallistumisen epätarkoituksenmukaiseksi.
12. Vierasesine tai implantti, joka ei ole MRI turvallinen

E.5 End points

E.5.1

Primary end point(s)

Global fractional anisotropy of white matter of diffusion tensor imaging (DTI). Hypothesis: White matter damage is less severe in xenon treated patients, i.e. global fractional anisotropy is significantly higher in the xenon group than in the control group as assessed with the 1st MRI within 48-96 hours after onset of SAH symptoms.

Selvittää ksenonin aivoja suojaavat ominaisuudet lukinkalvonalainen -verenvuotopotilailla
Primaari päätetapahtuma: Valkean aineen vaurio on vähäisempi ksenonilla hoidetuilla potilailla, eli aivojen valkean aineen magneettikuvauksella 48-96 tuntia oireiden alusta saatu globaali fraktioitu anisotropia arvo on merkittävästi korkeampi ksenonpotilailla.

E.5.1.1

Timepoint(s) of evaluation of this end point

48-96 hours after onset of SAH symptoms.

48-96 tuntia oireiden alusta

E.5.2

Secondary end point(s)

Fractional anisotropy of white matter at cerebellum and/or at corpus callosum
Exploratory endpoints: 1. Composite of radiological EBI (i.e. the 1st MRI) and DCI (Criterion of DCI: 1. a new focal neurological deficit/decrease in level of consciousness not due to other causes, e.g. hydrocephalus, seizures, metabolic derangement, infection, sedation, 2. a new infarct on follow-up imaging after 4 days post-SAH, i.e. 2nd MRI, or 3. both 1 and 2), and poor outcome (good: mRS 0-2; poor: mRS 3-6) at 3-months and at 1 year. 3. Neurogenic Stress Cardiomyopathy and Stunned Myocardium (i.e. myocardial injury caused by sympathetic storm and autonomic dysregulation with hs-troponin elevation, left ventricular dysfunction or ECG changes): 4. ICP level 5. Need for ICP therapies (hypothermia, decompressive craniotomy); 6. Duration of therapy for ICP control/monitoring; 7: Plasma catecholamine level; 8. Development of prognostication models for EBI and DCI and long-term outcome at 1 and 2 years after SAH by combining data of brain imaging, clinical data (including Turku Aneurysm Data) and metabolomics; 9. MRI parameters; 10. Metabolomics of plasma and spinal fluid (i.e. between xenon and control groups, between patients with and without EBI and/or DCI, between survivors and non-survivors at 90 days, at 1 year and at 2 years after onset of SAH symptoms; 11. Activity of microglia cells

1. Pikkuaivojen ja corpus callosumin valkean aineen fraktioitu anisotropia
Eksploratiiviset päätetaphtumat: 1. Radiologisesti havaittava varhainen aivovaurio ja/tai myöhäinen aivojen hapenpuute (DCI) (DCI kriteerit: 1. uusi paikallinen neurologinen puutosoire/tajunnan tason lasku ilman muuta syytä esimerkiksi hydrocephalus, kouristelu, metabolinen häiriö, infektio, sedaatio, 2. uusi infarkti seurannan aikana 4 päivää tai myöhemmin vuodon jälkeen, tai 3. 1 ja 2, ja huono neurologinen lopputulema (hyvä: mRS 0-2; huono: mRS 3-6) 3 kk ja vuoden kuluttua vuodosta)
2. Neurogenic Stress Cardiomyopathy and Stunned Myocardium (so. sydäninfarkti sympaattisen myrskyn ja autonomisen säätelyhäiriön takia yhdessä hs-troponiinin nousun, vasemman kammion vajaatoiminnan tai EKG muutosten kanssa)
3. Aivopaineen taso; aivopaineen hoitojen tarve ja kesto (hypothermia, dekompressiivinen kraniotomia)
4. Plasman katekoliamiinitaso

Muut tavoitteet:
1. Luodaan ennusteellisia malleja aikaiselle aivovauriolle (EBI), myöhäiselle aivojen hapenpuutteelle (DCI) ja pitkäaikaiselle selviämiselle 3 kuukauden, 1 vuoden ja 2 vuoden kuluttua SAV oireiden alusta. Tutkimusta tehdään yhdistämällä: i) aivokuvantaminen, ii) kliininen informaatio, iii) plasman ja likvorin metabolomiikka.
2. Selvittää metabolomiikan, aivokuvantamisten ja kliinisten muuttujien eroja interventioryhmien välillä.
3. Selvittää metabolomiikan, aivokuvantamisten ja kliinisten muuttujien eroja neurologisesti hyvin ja huonosti selvinneiden välillä 3 kuukauden, 1 vuoden ja 2 vuoden kuluttua SAV oireiden alusta.
4. Selvittää PET-kuvauksella mikrogliasoluaktivaation eroja interventioryhmien välillä

Ennustemallien luomisessa käytetään hyväksi Turku Aneurysma Data (TAD) pankkia, johon on kerätty kattavasti 2600 aneurysmapotilaan tiedot. Tiedostoon on kerätty yhteensä 70 miljoonaa tapahtumaa näiltä potilailta. Keinoälyä ja koneoppimista sovelletaan DAT tiedostoon, jonka tavoitteena on luoda ennustemalleja. Näiden ennustemallien diagnostista kykyä testataan TAD tiedostosta valitussa validaatiokohortissa ja tämän tutkimuksen potilailla.

E.5.2.1

Timepoint(s) of evaluation of this end point

During first 6 weeks after onset of SAH symtoms and during a follow-up of one year and at 2 years after onset of SAH symptoms

Ensimmäisen 6 viikon aikana, vuoden seurannan aikana ja 2 vuoden kuluttua oireiden alusta

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

Yes

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

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

Normaali hoito ilma/happiseoksella ja normotermiassa ilman ksenonia

Standard treatment with air/oxygen and normothermia and without xenon

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

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

After follow-up of 2 years after onset of SAH symptoms

Kahden vuoden seurannan jälkeen oireiden alusta

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:

140

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

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

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

160

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

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-09-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-06-09

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

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