Clinical Trials Register

Summary
EudraCT Number:	2012-003349-13
Sponsor's Protocol Code Number:	NOG112264
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:	2012-12-11
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

2012-003349-13

A.3

Full title of the trial

Study NOG112264, a Phase II Study of Ozanezumab
(GSK1223249) versus Placebo in the Treatment of Amyotrophic
Lateral Sclerosis

Studio NOG112264, uno studio di Fase II su ozanezumab (GSK1223249) a confronto con placebo nel trattamento della sclerosi laterale amiotrofica.

A.3.1

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

a Phase II Study of Ozanezumab
(GSK1223249) versus Placebo in the Treatment of Amyotrophic
Lateral Sclerosis

studio di Fase II su ozanezumab (GSK1223249) a confronto con placebo nel trattamento della sclerosi laterale amiotrofica.

A.3.2

Name or abbreviated title of the trial where available

Ozanezumab Phase II study in patients with ALS

Studio di fase II sull'Ozanezumab in pazienti SLA

A.4.1

Sponsor's protocol code number

NOG112264

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	GLAXOSMITHKLINE RESEARCH & DEVELOPMENT LTD.
B.1.3.4	Country	United Kingdom
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	GlaxoSmithKline
B.4.2	Country	China
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	GlaxoSmithKline
B.5.2	Functional name of contact point	GSK Clinical Support Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	GlaxoSmithKline, Iron Bridge Road, Stockley Park
B.5.3.2	Town/ city	Uxbridge, Middlesex
B.5.3.3	Post code	UB11 1BU
B.5.3.4	Country	Italy
B.5.4	Telephone number	+44 (0)20 8990 4466
B.5.5	Fax number	+44 (0)20 8990 1234
B.5.6	E-mail	GSKClinicalSupportHD@gsk.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/3/10/797 - EMA/OD/060/10
D.3 Description of the IMP
D.3.1	Product name	Ozanezumab
D.3.2	Product code	GSK1223249
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	1310680-64-8
D.3.9.2	Current sponsor code	GSK1223249
D.3.9.3	Other descriptive name	Immunoglobulin G1, anti (protein Nogo A) (human Mus musculus monoclonal heavy
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	15
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)	Yes
	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	Yes
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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Amyotrophic Lateral Sclerosis (ALS)

Sclerosi Laterale Amiotrofica (SLA)

E.1.1.1

Medical condition in easily understood language

ALS is a progressive, neurodegenerative disorder characterised by degeneration/death of motor neurones in the brain and spinal cord, resuting in severe disability and death

La SLA è una patologia neurodegenerativa progressiva che colpisce i motoneuroni, cioè le cellule neuronali deputate alla trasmissione dell’impulso nervoso alla muscolatura volontaria.

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	14.1
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to assess the effect of ozanezumab on the physical function and survival of ALS subjects over a treatment period of 48 weeks. Function will be measured using the Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R).

L’obiettivo primario è di valutare l’effetto di ozanezumab, somministrato per via endovenosa (e.v.) alla dose di 15 mg/kg una volta ogni 2 settimane, per 48 settimane, sulla funzionalità fisica(scala ALSFRS_R) e sulla sopravvivenza dei pazienti con SLA a confronto con placebo.

E.2.2

Secondary objectives of the trial

Secondary objectives include the evaluation of other clinical outcomes associated with ALS (respiratory function, muscle strength, progression free survival and overall survival) in support of the primary objective. Quality of life, safety, tolerability, immunogenicity and pharmacokinetics (ozanezumab and riluzole) will also be assessed.

Gli obiettivi secondari comprendono la valutazione dell’effetto di ozanezumab su altri esiti clinici associati alla SLA a supporto dell’obiettivo primario. Saranno inoltre valutate la qualità della vita, la sicurezza di impiego, la tollerabilità, l’immunogenicità e la farmacocinetica (PK) di ozanezumab.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients with diagnosis of familial or sporadic ALS, defined as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the revised World Federation of Neurology El Escorial criteria [Rix Brooks, 2000].2. Onset of muscle weakness no more than 30 months before screening visit.3. SVC of at least 65% predicted for gender, age, ethnicity and height at Screening.4. If on riluzole, the dose must have been stable for at least 28 days prior to Baseline visit.5. Age 18 – 80 years inclusive.6. Female subjects may participate if they are of non-child-bearing potential or if they are of child-bearing potential and agree to satisfy one of the requirements for contraception listed in Appendix 4 (Section 11.4)during the study and 4 months after the last dose to avoid pregnancy. Women of childbearing potential must have a negative pregnancy test and be non-lactating.7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT)≤ 2x upper limit of normal (ULN); alkaline phosphatase and bilirubin ≤ 1.5xULN. 8. QTc (both QTcB and QTcF) <450 milliseconds (msec) or <480 msec for subjects with Bundle Branch Block at Screening and Baseline (average from triplicate ECGs).

1. pazienti con diagnosi di SLA familiare o sporadica, definita come malattia che soddisfa i criteri diagnostici di SLA possibile, probabile con supporto di dati di laboratorio, probabile, definita secondo i criteri rivisti ‘World Federation of Neurology El Escorial’; 2. insorgenza di debolezza muscolare non oltre i 30 mesi prima della visita di screening; 3. capacita vitale inspiratoria lenta(SVC) alla visita di screening di almeno il 65% del valore predetto per sesso, età, etnia e altezza; 4. se in trattamento con riluzolo, il dosaggio deve essere stabile da almeno 28 giorni prima della visita basale; 5. età compresa tra 18 e 80 anni, estremi inclusi. 6. i soggetti di sesso femminile possono partecipare se non potenzialmente in grado di avere figli o, se potenzialmente in grado di avere figli, d’accordo a soddisfare uno dei requisiti per la contraccezione elencati nell’Appendice 4 (Sezione 11.4) del protocollo nel corso dello studio e per 4 mesi dopo l’ultima somministrazione, al fine di evitare una gravidanza. Le donne potenzialmente in grado di avere figli devono avere un test di gravidanza negativo e non essere in allattamento; 7. valore di aspartato aminotransferasi (AST) o alanina aminotranferasi (ALT) < o = 2 volte il limite superiore di normalità (Upper Normal Limit – ULN); fosfatasi alcalina e bilirubina < o = 1.5xULN. 8. QTc (sia QTcB che QTcF) < 450 millisecondi (msec) o < 480 msec per soggetti con blocco di branca allo screening e al basale (media di tre ECG).

E.4

Principal exclusion criteria

1. Patients with other neuromuscular disorders (including a history of polio), which in the opinion of the investigator could have contributed to the muscular atrophy or weakness caused by ALS or could have any other effect on the study efficacy or safety assessments that in the opinion of the investigator would impact participation in the study. 2. Patients with primary lateral sclerosis, monomelic ALS, ALS Parkinsonism dementia complex. 3. Patients requiring non-invasive or mechanical ventilation (noninvasive ventilation for sleep apnoea is allowed subject to discussion with Medical Monitor). 4. Patients on diaphragmatic pacing. 5. Presence of any of the following clinical conditions: a. Drug abuse or alcoholism (according to Diagnostic and Statistical Manual of Mental Disorders –Fourth Edition [DSM-IV] criteria). b. Uncontrolled hypertension despite optimal antihypertensive treatment; unstable cardiovascular, pulmonary, renal, endocrine or hematologic condition; current malignancy. c. Active major infectious disease e.g. systemic infections with visceral involvement (pneumonia, pyelonephritis, endocarditis) and/or septicaemia. d. Unstable psychiatric illness, such as psychosis or untreated major depression, within 90 days of the Screening visit. 6. Subjects, who in the investigator's judgement, pose a significant suicide risk. 7. Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones), positive Hepatitis B surface antigen or Hepatitis C antibody test. 8. Subjects who have participated in a clinical trial involving receipt of a biopharmaceutical product (recombinant proteins, monoclonal antibodies, blood products, sera, allergens, and gene and cell therapy products) within 6 months prior to the first dosing day. 9. Patients who have received any type of vaccination within 2 weeks prior to study drug administration. 10. Chronic (>3 months) use of systemic immunosuppressants including systemic steroids. 11. Exposure to non-biological experimental agents (including investigational products and marketed medications used off-label) 1 month or 5 half-lives prior to Baseline visit (whichever is longer). 12. History of sensitivity to ozanezumab, or components thereof, or a history of other allergies that, in the opinion of the investigator, contraindicates participation in the study.

1. pazienti con altri disturbi neuromuscolari (inclusa anamnesi positiva per poliomielite), che, a giudizio dello Sperimentatore, potrebbero aver contribuito all’atrofia muscolare o alla debolezza causata dalla SLA o, che potrebbero avere qualsiasi altro effetto sulle valutazioni di efficacia o di sicurezza dello studio che a giudizio dello Sperimentatore avrebbero un impatto sulla partecipazione allo studio; 2. pazienti con sclerosi laterale primaria, SLA monomelica, complesso SLA-Parkinson-demenza. 3. pazienti che richiedono ventilazione non invasiva o meccanica (la ventilazione non invasiva per l’apnea notturna è consentita previa discussione con il Medical Monitor); 4. pazienti con pace-maker diaframmatico; 5. presenza di una delle seguenti condizioni patologiche: a. abuso di droghe o alcolismo (secondo i criteri del Diagnostic and Statistical Manual of Mental Disorders – Quarta Edizione [DSM-IV]), b. ipertensione non controllata nonostante trattamento antiipertensivo ottimale; condizione cardiovascolare, polmonare, renale, endocrina o ematologica instabile; patologia tumorale in corso, c. malattia infettiva rilevante attiva, ad esempio infezioni sistemiche con coinvolgimento viscerale (polmonite, pielonefrite, endocardite) e/o setticemia, d. malattia psichiatrica instabile, come psicosi o depressione maggiore non trattata, nei 90 giorni precedenti la visita di screening; 6. soggetti che, a giudizio dello Sperimentatore, sono a rischio significativo di suicidio; 7. anamnesi positiva per malattia epatica in corso o cronica, anomalie epatiche o biliari note (ad eccezione della sindrome di Gilbert o dei calcoli alla cistifellea asintomatici), test positivo per antigene di superficie dell’epatite B o per anticorpi per l’epatite C; 8. soggetti che hanno partecipato ad uno studio clinico che implicava l’assunzione di un prodotto biofarmaceutico (proteine ricombinanti, anticorpi monoclonali, emoderivati, sieri, allergeni e prodotti per terapia genica o cellulare) nei 6 mesi precedenti il primo giorno di somministrazione; 9. pazienti che sono stati sottoposti a qualsiasi tipo di vaccinazione nelle 2 settimane precedenti la somministrazione del farmaco in studio; 10. utilizzo cronico (> 3 mesi) di agenti immunosoppressori sistemici, compresi steroidi sistemici; 11. esposizione ad agenti sperimentali non-biologici (compresi prodotti sperimentali e farmaci in commercio utilizzati off-label) 1 mese o 5 emivite prima della visita basale (a seconda di quale dei due periodi è più lungo); 12. anamnesi positiva per ipersensibilità ad ozanezumab o ai suoi componenti, o per altre allergie che, a giudizio dello Sperimentatore, costituiscono una controindicazione alla partecipazione allo studio.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the joint rank scores for combined analysis of function and survival (also called joint rank analysis). Function is measured using the amyotrophic lateral sclerosis functional rating scale – revised (ALSFRS-R)

L’endpoint primario di efficacia per questo studio è il punteggio combinato di funzionalità, misurata con punteggio ALSFRS-R e sopravvivenza globale nel tempo a seguito del trattamento con ozanezumab o placebo per 48 settimane.

E.5.1.1

Timepoint(s) of evaluation of this end point

ALSFRS-R will be assessed every 4 weeks for 48 weeks. Primary endpoint evaluated at Week 48.

ALSFRS-R viene valutata ogni 4 settimane per 48 settimane. L'endpoint primario viene valutato a 48 settimane.

E.5.2

Secondary end point(s)

Secondary endpoints include: Change from Baseline in ALSFRS-R, Slow Vital Capacity (SVC), Muscle Strength (HHD), Amyotrophic lateral sclerosis assessment questionnaire-40 (ALSAQ-40), EuroQoL – Short form EQ-5D-L, ; Proportion of clinical global impression - improvement (CGI-I) responders; Overall survival and progression free survival.

Gli endpoint di efficacia comprendono: o variazione dal basale alla Settimana 48 nel punteggio totale ALSFRS-R o variazione dal basale alla Settimana 48 della funzionalità respiratoria (capacità vitale inspiratoria lenta) o variazione dal basale alla Settimana 48 della forza muscolare (misurata tramite dinamometro), o variazione dal basale alla Settimana 48 della condizione clinica globale (scala CGI-I), o valutazione della sopravvivenza globale o valutazione del tempo di sopravvivenza senza progressione della malattia o valutazioni degli esiti sulla salute alla settimana 48 con questionario EuroQoL abbreviato EQ-5D-L o valutazioni degli esiti sulla salute alla settimana 48 con questionario di valutazione specifico per la SLA (Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 - ALSAQ-40). Gli endpoint di safety comprendono: o incidenza e gravità degli eventi avversi (Adverse Event – AE), o variazione dal basale dei segni vitali o variazione dal basale dei test clinici di laboratorio, o variazione dal basale dell’elettrocardiogramma (ECG). Altri endpoint secondari comprendono: o misure di farmacocinetica di ozanezumab o conferma di assenza di interazione tra ozanezumab e riluzolo o valutazione di immunogenicità: incidenza di anticorpi anti-ozanezumab Altre valutazioni dello studio: o misura dei livelli sierici di biomarcatori candidati per la SLA o C-SSRS valutazione del rischio di ideazione e comportamento suicidari o ricerca farmacogenetica (opzionale per il paziente)

E.5.2.1

Timepoint(s) of evaluation of this end point

Endpoints evaluation at Week 48 (and week 60 for overall survival). Actual assessments administered every 4 weeks or 3 months depending on assessment.

Gli endpoints vengono valutati alla settimana 48 (la sopravvivenza alla settimana 60). Valutazioni sono di fatto effettuate ogni 4 settimana o ogni 3 mesi a seconda dell'esame.

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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

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

Australia

Canada

Japan

Korea, Republic of

United States

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

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

Number of subjects for this age range:

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:

279

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

162

F.4.2.2

In the whole clinical trial

294

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)

Following study completion, investigators should continue treatment of the subject's condition according to best accepted clinical practices with consideration to available licensed products for the treatment of ALS. Post-study treatment with ozanezumab will not be provided by GSK as sufficient efficacy and safety data is not yet available to confirm a positive benefit/risk profile of ozanezumab in ALS patients.

Alla conclusione dello studio,lo sperimentatore continuerà a curare il soggetto secondo la migliore pratica clinica corrente considerando i prodotti in commercio per il trattamento della SLA. GSK non fornisce ozanezumab dopo lo studio in quanto non sono disponibili dati sufficienti sull'efficacia e la sicurezza di ozanezumab per confermare un profilo di rischio/beneficio positivo nel trattamento di pazienti con SLA.

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

2012-10-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-01-28

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