Clinical Trials Register

Summary
EudraCT Number:	2018-002939-21
Sponsor's Protocol Code Number:	AARON
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-10-04
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

Germany - PEI

A.2

EudraCT number

2018-002939-21

A.3

Full title of the trial

An Open-Label Phase II Study of Relatlimab (BMS-986016) with Nivolumab (BMS- 936558) in Combination with 5-Azacytidine for the Treatment of Patients with Refractory/Relapsed Acute Myeloid Leukemia and Newly Diagnosed Older Acute Myeloid Leukemia Patients

Open-Label-Phase II-Studie zur Anwendung von Relatlimab (BMS-986016) und Nivolumab (BMS-936558) in Kombination mit 5-Azacitidin zur Behandlung von Patienten mit refraktärer/rezidivierter Akuter Myeloischer Leukämie und von älteren Patienten mit neu diagnostizierter Akuter Myeloischer Leukämie

A.3.1

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

Relatlimab, Nivolumab and 5-Azacytidine in Patients with AML

Relatlimab, Nivolumab und 5-Azacitidin bei Patienten mit AML

A.3.2

Name or abbreviated title of the trial where available

AARON

A.4.1

Sponsor's protocol code number

AARON

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	Klinikum der Universität München
B.1.3.4	Country	Germany
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	Bristol-Myers Squibb GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Klinikum der Universität München
B.5.2	Functional name of contact point	Translational Cancer Immunotherapy
B.5.3	Address:
B.5.3.1	Street Address	Marchioninistr. 15
B.5.3.2	Town/ city	Munich
B.5.3.3	Post code	81377
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4989440073133
B.5.5	Fax number	+4989440076133
B.5.6	E-mail	veit.buecklein@med.uni-muenchen.de

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	Relatlimab
D.3.2	Product code	BMS-986016
D.3.4	Pharmaceutical form	Concentrate for dispersion 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.3.8	INN - Proposed INN	Relatlimab
D.3.9.2	Current sponsor code	BMS-986016
D.3.9.4	EV Substance Code	SUB168199
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	10
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	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	Monoclonal antibody
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	Opdivo
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	Concentrate for 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.3.8	INN - Proposed INN	Nivolumab
D.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	BMS-936558
D.3.9.3	Other descriptive name	NIVOLUMAB
D.3.9.4	EV Substance Code	SUB122750
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	10
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	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	Monoclonal antibody

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

Subjects with Acute myeloid leukemia

Patienten mit akuter myeloischer Leukämie

E.1.1.1

Medical condition in easily understood language

Subjects with relapsed or refractory (r/r) Acute myeloid leukemia (AML) or Patients aged ≥65 years with previously untreated AML who are unfit for or decline standard induction therapy.

Patienten mit rezidivierter oder refraktärer akuter myeloischer Leukämie (AML) oder Patienten ≥65 Jahre mit AML, die für eine Standard-Induktionschemotherapie nicht in Frage kommen oder diese ablehnen

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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	10001941
E.1.2	Term	AML
E.1.2	System Organ Class	100000004864

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

Lead-in-phase:
Maximum tolerated dose and dose-limiting toxicities of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML
Expansion phase:
• Objective response rate to treatment with relatlimab + nivolumab + 5- azacytidine in patients with R/R AML
• ORR to treatment with relatlimab + nivolumab + 5- azacytidine in older patients (≥65 years) with newly diagnosed AML

Lead-in-Phase:
• Bestimmung der maximal tolerablen Dosis (MTD) und dosislimitierender Toxizitäten (DLT) von Relatlimab in Kombination mit Nivolumab und 5-Azacitidin bei Patienten mit r/r AML.
Expansionsphase:
• Bestimmung der Gesamtansprechrate (overall response rate, ORR) unter Therapie mit Relatlimab + Nivolumab + 5- Azacitidin bei Patienten mit r/r AML.
• Bestimmung der ORR unter Therapie mit Relatlimab + Nivolumab + 5-Azacitidin bei Patienten ≥65 Jahren mit neu diagnostizierter AML.

E.2.2

Secondary objectives of the trial

• % of grade I/II and grade III/IV toxicities for patients with R/R AML on therapy with relatlimab + nivolumab + 5- azacytidine
• % of grade I/II and grade III/IV toxicities for older patients with newly diagnosed AML on therapy with relatlimab + nivolumab + 5-azacytidin
• Number of patients with R/R AML who achieve a HI in platelets, hemoglobin, or ANC on therapy with relatlimab + nivolumab + 5-azacytidine
• Number of patients with R/R AML who achieve ≥50% reduction in blasts on therapy with relatlimab + nivolumab + 5-azacytidine.
• Number of older patients with newly diagnosed AML who achieve an HI in platelets, hemoglobin, or ANC on therapy with relatlimab + nivolumab + 5-azacytidine
• Number of older patients with newly diagnosed AML who achieve ≥50% reduction in blasts on therapy with relatlimab + nivolumab + 5-azacytidine
• Duration of response, DFS, and OS of patients with R/R AML treated with relatlimab + nivolumab + 5-azacytidine

• Bestimmung der Sicherheit der Therapie mit Relatlimab + Nivolumab + 5-Azacitidin bei Patienten mit r/r AML
• Bestimmung der Sicherheit der Therapie mit Relatlimab + Nivolumab + 5-Azacitidin bei Patienten ≥65 Jahren mit neu diagnostizierter AML
• Bestimmung der Anzahl an Patienten mit r/r AML, die eine hämatologische Verbesserung (hematologic improvement, HI) oder eine Reduktion des Blastenanteils um ≥50% unter Therapie mit Relatlimab + Nivolumab + 5-Aza erreichen.
• Bestimmung der Anzahl an Patienten ≥65 Jahren mit neu diagnostizierter AML, die eine HI oder eine Reduktion des Blastenanteils um ≥50% unter Therapie mit Relatlimab + Nivolumab + 5-Aza erreichen.
• Bestimmung der Dauer des Ansprechens, des erkrankungsfreien Überlebens und des Gesamtüberlebens bei Pat. mit r/r AML unter Therapie mit Relatlimab + Nivolumab + 5-Aza.
• Bestimmung der Dauer des Ansprechens, DFS und OS bei Pat. ≥65 Jahren mit neu diagnostizierter AML unter Therapie mit Relatlimab + Nivolumab + 5-Aza.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Cohort 1 (R/R AML):
• Patients with AML who have failed first line therapy (other than hydroxyurea) or patients who have relapsed after achieving a CR, CRp, or CRi.
• Patients with AML who have failed up to one prior salvage therapy (i.e. salvage 1 or 2 status) will also be eligible. Allogeneic stem cell transplant for patients in remission at the time of transplant will not be considered a salvage regimen. Hydroxyurea if used alone will not be considered a salvage regimen.
Cohort 2 (frontline older AML):
• Patients aged ≥65 years with previously untreated AML who are unfit for or decline standard induction therapy.
• Prior therapy with hydroxyurea, biological or targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is allowed, however, prior therapy with chemotherapy agents for the disease under study is not allowed.
All Cohorts:
• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2
• Adequate organ function
• Patients must provide written informed consent

Kohorte 1 (r/r AML):
• Patienten mit AML, die unter Erstlinientherapie (ausgenommen Hydroxyurea) ein Therapieversagen zeigen oder Patienten, die ein Rezidiv nach Erreichen einer CR/CRi erleiden und unter bis zu einer vorhergehenden Salvagetherapie ein Therapieversagen zeigen
Kohorte 2 (Erstlinientherapie bei älteren AML-Patienten):
• Patienten mit ≥65 Jahren mit unbehandelter AML, die für eine Standardinduktionstherapie nicht in Frage kommen oder diese verweigern
Allgemeine Einschlusskriterien:
• Alter ≥18 Jahre
• ECOG Performance Status ≤2
• Adäquate Organfunktion:
– Gesamtbilirubin ≤2 x ULN (≤3 × ULN, falls durch leukämische Infiltration oder M. Meulengracht bedingt)
– AST und ALT ≤2.5 × ULN (≤5.0 × ULN falls durch leukämische Infiltration bedingt)
– Serumkreatinin ≤2 × ULN oder glomeruläre Filtrationsrate (GFR) ≥50 mL/h
• Adäquate Herzfunktion: TTE mit dokumentierter LVEF ≥50% innerhalb von sechs Monaten vor erster Studienmedikations-Gabe
• Zeitabstand zur Vortherapie von mindestens zwei Wochen ODER mindestens 5 Halbwertszeiten
• GvHD Grad ≤A unter Therapie mit ≤10 mg Prednison ohne weitere Immunsuppression (Tacrolimus, Ciclosporin, etc.)
• Schriftliches Einverständnis
• Negativer Schwangerschaftstest und adäquate Kontrazeptionsmethode für weibliche Studienteilnehmer in gebärfähigem Alter, adäquate Kontrazeptionsmethode für männliche Studienteilnehmer

E.4

Principal exclusion criteria

• Patients with APL.
• Patients with known allergy or hypersensitivity to nivolumab, 5-azacytidine, relatlimab, or any
of their components.
• Patients with a history of life-threatening toxicity related to prior immune therapy (e.g. anti- CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T cell costimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hormone replacement after endocrinopathy).
• Patients who have previously been treated with immunotherapeutic drugs targeting PD-1/PD-L1 in combination with 5-azacytidine.
• Patients who have previously been treated with LAG-3 targeted agents.
• Patients with a known history of severe interstitial lung disease or severe pneumonitis.
• Patients with an active, known or suspected history of any autoimmune disease

• Akute Promyelozytenleukemie (APL)
• Biphänotypische oder bilineare Leukämie
• Bekannte Allergie oder Unverträglichkeit gegen 5- Azacitidine, Nivolumab, Relatlimab, oder einen ihrer Bestandteile
• Anamnestisch vorbekannte lebensgefährliche Nebenwirkung in Zusammenhang mit einer vorhergegangenen Immuntherapie
• Vorhergegangene Therapie mit Immuntherapeutika gegen OD-1/PD-L1 in Kombination mit 5-Azacitidine
• Vorhergegangene Therapie mit Medikamenten, die gegen LAG-3 gerichtet sind
Anamnestisch vorbekannte schwere interstitielle Lungenerkrankung oder schwere Pneumonitis
• Anamnestisch (aktive, vorbekannte oder vermutete) Vorerkrankung einer der folgenden Autoimmunerkrankungen:
– Chronisch-entzündliche Darmerkrankung
– Rheumatoide Arthritis
– Progressive systemische Sklerose
– Systemischer Lupus erythematodes
– Autoimmunvaskulitis
• Aktive
• Aktive
unkontrollierte Pneumonitis unkontrollierte Infektion
• Symptomatischer oder unzureichend kontrollierter
leukämischer ZNS-Befall
• Anamnestisch vorbekannte Encephalitis, Meningitis oder unkontrolliertes Krampfleiden im Jahr vor Einwilligung zur Studienteilnahme
• Unkontrollierte oder signifikante kardiovaskuläre V orerkrankung
• Troponin T (TnT) oder I (TnI) > 2 × institutionelle ULN
• Z.n. Organtransplantation
• Allgene hämatopoetische Stammzelltransplantation innerhalb der letzten 100 Tage vor Erstgabe der Studienmedikation
• aktive GvHD > Grad A
• Vorbekannte Seropositivität für Humanes Immundefizienz-
Virus (HIV)
• Anamnestisch vorbekannte Positivität für Hepatitis B mit nachweisbarem HBs-Antigen oder aktive Hepatitis C- Infektion
• Anderer medizinischer, psychologischer oder sozialer Zustand, der mit der Studienteilnahme oder Compliance interferieren, oder die Patientensicherheit gefährden könnte
• Patienten, die nicht bereit oder in der Lage sind, sich an die Vorgaben des Studienprotokolls zu halten
Schwangere oder stillende Patientinnen
• Gefängnisinsassen oder Patienten, die gegen ihren Willen untergebracht sind

E.5 End points

E.5.1

Primary end point(s)

Lead-in phase: MTD and DLT of relatlimab in combination with nivolumab and 5-azacytidine in patients with R/R AML
Expansion phase: ORR to treatment with relatlimab + nivolumab + 5-azacytidine in patients with R/R AML
Expansion phase: ORR to treatment with relatlimab + nivolumab + 5-azacytidine in older patients (≥65 years) with newly diagnosed AML

E.5.1.1

Timepoint(s) of evaluation of this end point

Lead-in phase: after completion of 1st cycle of treatment and evaluation of DLTs in 6-12 patients (number of subjects depending on DLT occurrence)
Expansion phase: after completion of study (30 patients)

E.5.2

Secondary end point(s)

• To determine the safety of therapy with relatlimab + nivolumab + 5-azacytidine for patients with R/R AML
• To determine the safety of therapy with relatlimab + nivolumab + 5-azacytidine for older patients with newly diagnosed AML
• To determine the number of patients with R/R AML who achieve a hematologic improvement (HI) in platelets, hemoglobin, or absolute neutrophil count (ANC) and the number of patients with R/R AML who achieve ≥50% reduction in blasts on therapy with relatlimab + nivolumab + 5-azacytidine.
• To determine the number of older patients with newly diagnosed AML who achieve an HI in platelets, hemoglobin, or ANC and the number of older patients with newly diagnosed AML who achieve ≥50% reduction in blasts on therapy with relatlimab + nivolumab + 5-azacytidine.
• To assess the duration of response, disease-free survival (DFS), and overall survival (OS) of patients with R/R AML treated with relatlimab + nivolumab + 5-azacytidine.
• To assess the duration of response, DFS, and OS in older patients with newly diagnosed AML treated with relatlimab + nivolumab + 5-azacytidine.

E.5.2.1

Timepoint(s) of evaluation of this end point

after completion of study (30 patients)

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

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

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

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

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

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

F.4.2.2

In the whole clinical trial

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)

treatment according to clinical routine, which might include approved agents (e.g. cytarabine), participation in another clinical trial or best supportive care.

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

2020-04-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-06-15

P. End of Trial
P.	End of Trial Status	Ongoing

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