Clinical Trials Register

Summary
EudraCT Number:	2012-002487-27
Sponsor's Protocol Code Number:	1230.14
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-11-29
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

Spain - AEMPS

A.2

EudraCT number

2012-002487-27

A.3

Full title of the trial

A phase III randomised, double-blind, controlled, parallel group study of intravenous volasertib in combination with subcutaneous low-dose cytarabine vs. placebo + low-dose cytarabine in patients >= 65 years with previously untreated acute myeloid leukaemia, who are ineligible for intensive remission induction therapy.

Ensayo clínico de fase III, aleatorizado, doble ciego, controlado, paralelo, de volasertib intravenoso en combinacion con dosis bajas de citarabina subcutánea vs. placebo + dosis bajas de citarabina en pacientes >= 65 años con leucemia mieloide aguda previamente no tratada, que no puedan recibir tratamiento intensivo de inducción de la remisión

A.3.1

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

A study of volasertib in combination with low-dose cytarabine in patients aged 65 years and above with previously untreated acute myeloid leukaemia, who are ineligible for intensive remission induction therapy

Ensayo de volasertib en combinación con dosis bajas de citarabina en pacientes de 65 años o más con leucemia mieloide aguda previamente no tratada, que no puedan recibir tratamiento intensivo de inducción de la remisión.

A.3.2

Name or abbreviated title of the trial where available

POLO-AML-2

A.4.1

Sponsor's protocol code number

1230.14

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	Boehringer Ingelheim España, S.A
B.1.3.4	Country	Spain
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	Boehringer Ingelheim España, S.A
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	QRPE PSC CT Information Disclosure
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.4	Telephone number	+1800243 0127
B.5.5	Fax number	+1800821 7119
B.5.6	E-mail	clintriage.rdg@boehringer-ingelheim.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Volasertib
D.3.2	Product code	BI 6727
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.3.8	INN - Proposed INN	volasertib
D.3.9.3	Other descriptive name	BI 6727
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	2
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	Ara-cell 40 mg injection
D.2.1.1.2	Name of the Marketing Authorisation holder	cell pharm 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	Ara-cell 40 mg injection
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	cytarabine
D.3.9.1	CAS number	147-94-4
D.3.9.4	EV Substance Code	SUB06880MIG
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	40
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	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

previously untreated acute myeloid leukaemia in patients >= 65 years and ineligible for intensive remission induction therapy

pacientes de 65 años o más con leucemia mieloide aguda previamente no tratados y que no puedan recibir tratamiento intensivo de inducción de la remisión

E.1.1.1

Medical condition in easily understood language

acute myeloid leukaemia (previously untreated) in patients >= 65 years and ineligible for intensive remission induction therapy

pacientes de 65 años o más con leucemia mieloide aguda previamente no tratados y que no puedan recibir tratamiento intensivo de inducción de la remisión

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10000886
E.1.2	Term	Acute myeloid leukemia
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

To investigate the efficacy, of intravenous volasertib + subcutaneous low-dose cytarabine in patients >= 65 years of age with previously untreated acute myeloid leukaemia, ineligible for intensive remission induction therapy. Efficacy will be determined primarily based on remission rate (CR+CRi) and overall survival (OS).

Investigar la eficacia de volasertib por vía intravenosa + citarabina a dosis bajas administrada por vía subcutánea en pacientes ? 65 años con leucemia mieloide aguda no tratada previamente que no puedan ser elegidos para un tratamiento intensivo de inducción de la remisión. La eficacia se determinará principalmente por la tasa de remisión (CR+CRi) y por la supervivencia global (OS).

E.2.2

Secondary objectives of the trial

To investigate the safety, and pharmacokinetics of intravenous volasertib + subcutaneous low-dose cytarabine in patients >= 65 years of age with previously untreated acute myeloid leukaemia, ineligible for intensive remission induction therapy.

Investigar la seguridad y la farmacocinética de volasertib por vía intravenosa + citarabina a dosis bajas administrada por vía subcutánea en pacientes ? 65 años con leucemia mieloide aguda no tratada previamente que no puedan ser elegidos para un tratamiento intensivo de inducción de la remisión.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Age >= 65years.
2.Cytologically/histologically confirmed AML according to WHO classification; (except for acute promyelocytic leukaemia (APL)).
3.Previously untreated AML (except for hydroxyurea and/or corticosteroid therapy for no more than 28 days (cumulative)). Previous therapy for MDS is allowed.
4.Investigator considers patient ineligible for intensive remission induction therapy based on documented medical reasons (e.g. disease characteristics like AML genetics, type of AML (de novo or secondary), and patient characteristics like performance score, concomitant diagnoses, organ dysfunctions).
5.Patient is eligible for low dose cytarabine treatment.
6.Eastern co-operative oncology group (ECOG) performance score ? 2 at screening.
7.Signed and dated written informed consent by start date of Screening visit in accordance with GCP and local legislation.

1. Edad ? 65 años.
2. AML confirmada citológicamente/histológicamente según la clasificación de la OMS (excepto para la leucemia promielocítica aguda (APL)).
3. AML no tratada previamente (excepto tratamiento con hidroxiurea y/o corticosteroides durante un periodo no superior a 28 días (acumulativo)). Se permite tratamiento previo para el MDS.
4. El investigador considera que el paciente no es elegible para un tratamiento intensivo de inducción de la remisión basándose en razones médicas documentadas (p. ej. características de la enfermedad como la genética de AML, tipo de AML (de novo o secundaria), y características del paciente como la puntuación del estado funcional, diagnósticos concomitantes, disfunciones orgánicas).
5. Paciente es elegible para el tratamiento con LDAC.
6. Puntuación del estado funcional, según el Grupo oncológico cooperativo del este (ECOG), de ? 2 en el momento de la selección.
7. Consentimiento informado firmado y fechado antes de la fecha del inicio de la visita de selección conforme a las Buenas Prácticas Clínicas (GCP) y a la legislación local.

E.4

Principal exclusion criteria

1.Prior or concomitant chemotherapy for AML (with the exception of hydroxyurea and/or corticosteroid therapy for no more than 28 days (cumulative)).
2.Treatment with any investigational drug within 2 weeks before first administration of present trial drug.
3.Acute promyelocytic leukaemia (French-American-British (FAB) classification subtype M3).
4.Current clinical central nervous system (CNS) symptoms deemed by the investigator to be related to leukaemic CNS involvement (no lumbar puncture required, clinical assessment per investigator?s judgement is sufficient).
5.Hypersensitivity to one of the trial drugs or the excipients.
6.Severe illness or organ dysfunction involving the heart, kidney, liver or other organ system (e.g. active infection, clinically relevant impairment of cardiac function, severe heart failure/cardiac insufficiency, unstable angina pectoris or history of recent myocardial infarction), which in the opinion of the investigator precludes treatment with LDAC.
7.QTcF prolongation > 470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome).The QTcF will be calculated as the mean of the 3 ECGs taken at screening.
8.Total bilirubin > 3 x ULN.
9.Creatinine clearance (CLcr) < 30 ml/min (estimated creatinine clearance by the Cockcroft-Gault (C-G) equation.
10.Active hepatitis B or hepatitis C, or laboratory evidence for a chronic infection.
11.HIV infection.
12.Second malignancy currently requiring active therapy (except for hormonal/anti-hormonal treatment e.g. in prostate or breast cancer).
13.Any significant concurrent psychiatric disorder or social situation that according to the investigator?s judgement would compromise patient?s safety or compliance, interfere with consent, study participation, or interpretation of study results.
14.Known or suspected active alcohol or drug abuse.
15.Patient unable to comply with the protocol, in the opinion of the investigator.
16.Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second medically acceptable method of contraception during the trial and for a minimum of 6 months after study treatment .

1. Quimioterapia concomitante o previa para la AML (excepto el tratamiento con hidroxiurea y/o tratamiento con corticosteroides durante un periodo no superior a 28 días (acumulativo)).
2. Tratamiento con cualquier fármaco en fase de investigación en las dos semanas antes de la primera administración del presente fármaco del estudio.
3. Leucemia promielocítica aguda (clasificación franco-americana-británica (FAB) subtipo M3).
4. Síntomas clínicos actuales del sistema nervioso central (SNC) que el investigador considere relacionados con una afectación leucémica del SNC (no se requiere ninguna punción lumbar, es suficiente la evaluación clínica según el criterio del investigador).
5. Hipersensibilidad a alguno de los fármacos o excipientes del ensayo.
6. Enfermedad grave o disfunción orgánica que afecte al corazón, riñón, hígado o a otro sistema orgánico (p. ej. infección activa, empeoramiento clínicamente importante de la
función cardiaca, cardiopatía/insuficiencia cardiaca graves, angina de pecho inestable o antecedentes de un infarto de miocardio reciente) que según el investigador excluyan un tratamiento con LDAC.
7. Prolongación del intervalo QTcF > 470 ms o prolongación del intervalo QT que el investigador considere clinicamente relevante (p. ej. síndrome de QT largo congénito). El QTcF se calculará como la media de 3 registros de ECG en el momento de la selección.
8. Bilirrubina total > 3 veces el límite superior de la normalidad (ULN).
9. Aclaramiento de creatinina (CLcr) < 30 ml/min (aclaramiento de creatinina estimado según la ecuación de Cockcroft-Gault (C-G)
10. Hepatitis B o hepatitis C activas o evidencia de laboratorio de una infección crónica.
11. Infección por el VIH.
12. Segunda neoplasia maligna que requiera actualmente un tratamiento activo (excepto tratamiento hormonal/antihormonal, p. ej. en caso de cáncer de próstata o cáncer de mama).
13. Cualquier trastorno psiquiátrico concurrente significativo o situación social que según el criterio del investigador pudiese comprometer la seguridad del paciente o el cumplimiento, interferir en el consentimiento, la participación en el estudio o en la interpretación de los resultados del estudio.
14. Conocimiento o sospecha de alcoholismo o drogadicción activos.
15. Paciente incapaz de cumplir con el protocolo, según la opinión del investigador.
16. Pacientes varones con parejas con posibilidad de quedar embarazadas que no estén dispuestos a utilizar preservativos en combinación con un segundo método anticonceptivo aceptable, desde el punto de vista médico, durante el ensayo y durante un mínimo de 6 meses después del tratamiento del estudio.

E.5 End points

E.5.1

Primary end point(s)

Complete Remission (CR) and Complete Remission with incomplete blood count recovery (CRi), based on blinded central review.

Remisión Completa (CR) y Remisión Completa con una recuperación incompleta del hemograma (CRi), basada en una revisión central enmascarada

E.5.1.1

Timepoint(s) of evaluation of this end point

For assessment of the primary endpoint, remission rate, the baseline and response assessment bone marrow samples will be reviewed by a central laboratory. Response assessment is done at the end of every 2nd cycle during treatment period. In case of suspected disease progression a bone marrow examination should be performed as soon as possible.

Para evaluar el criterio principal de valoración, la tasa de remisión, las muestras tomadas en el momento basal y las muestras de la médula ósea de la evaluación de la respuesta serán revisadas por un laboratorio central. La evaluación de la respuesta se realiza al final de cada segundo ciclo durante el periodo de tratamiento. En caso de sospecha de progresión de la enfermedas se debe realizar un examen de la médula ósea lo antes posible.

E.5.2

Secondary end point(s)

-Key secondary endpoint: Overall Survival (OS).
-Secondary endpoints: Event-Free Survival (EFS), Relapse-Free Survival (RFS), safety, pharmacokinetics

? Variable secundaria clave de valoración: Supervivencia Global (OS).
? Criterios secundarios de valoración: Supervivencia libre de eventos (EFS), Supervivencia libre de recaídas (RFS)

E.5.2.1

Timepoint(s) of evaluation of this end point

OS: all randomised patients are followed until death, lost to follow-up or withdrawal of consent.
EFS: defined for all randomised patients, and measured from date of randomisation to date of progression or relapse, or death, whichever occurs first.
RFS: defined only for patients achieving CR or CRi; measured from date of remission until date of relapse or death. Relapse or progression are evaluated at each response assessment.

After end of active treatment follow-up visits will occur every 12 weeks.

All adverse events occurring during the trial will be collected.
Blood for PK will be collected at specified time points during C1 and C2 (optional at C4 and C6).

OS: todos los pacientes aleatorizados se siguen hasta que mueren, que se pierdan durante el seguimiento o si retiran el consentimiento.

EFS: definida para todos los pacientes aleatorizados, y medida desde la fecha de aleatorización hasta la fecha de progresión o recaída, o muerte, lo que ocurra primero.

RFS: definida solamente para los pacientes que alcancen CR o CRi; medida como la fecha de remisión hasta la fecha de recaída o muerte. La recaída o progresión se evalúan en cada evaluación de la respuesta.

Tras la finalización de las visitas de seguimiento con tratamiento activo que ocurrirán cada 12 semanas.

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Biomarker analyses

Analisis de biomarcadores

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.2.3.1

Comparator description

volasertib+dosis bajas de citarabian vs. placebo+dosis bajas de citarabina

volasertib + low dose cytarabine vs. placebo + low dose cytarabine

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

Argentina

Austria

Belgium

Brazil

Canada

Czech Republic

Finland

France

Germany

Greece

Hungary

India

Italy

Japan

Korea, Republic of

Mexico

Netherlands

Norway

Poland

Portugal

Romania

Russian Federation

South Africa

Spain

Taiwan

Thailand

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

The clinical trial will be considered completed as soon as the last patient has died or was lost to follow-up or as the predefined OS events are met.

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.1.1.1

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)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

660

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

460

F.4.2.2

In the whole clinical trial

660

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

2013-01-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-01-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-05-28

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