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    Summary
    EudraCT Number:2013-004864-69
    Sponsor's Protocol Code Number:HSJD-HR-NB-Ch14.18
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-04-01
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2013-004864-69
    A.3Full title of the trial
    Phase II single arm institutional study to assess Dinutuximab combined with the cytokines granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-2 in patients with high-risk neuroblastoma not eligible to other immunotherapy trials
    Ensayo Clínico de Fase II unicéntrico, no controlado, de Dinutuximab con las citoquinas factor estimulante de colonias de granulocitos y macrófagos (GM-CSF) e IL-2, en pacientes con neuroblastoma de alto riesgo que no son candidatos para otros ensayos de inmunoterapia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase II clinical trial of dinutuximab in high risk neuroblastoma.
    Ensayo clínico fase II de dinutuximab en neuroblastoma de alto riesgo.
    A.4.1Sponsor's protocol code numberHSJD-HR-NB-Ch14.18
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorFundació Sant Joan de Deu de Barcelona
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportFundació Sant Joan de Deu
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMFAR
    B.5.2Functional name of contact pointDpto Investigacion
    B.5.3 Address:
    B.5.3.1Street AddressSecretari Coloma 64-68 esc B entlo 5
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08024
    B.5.3.4CountrySpain
    B.5.4Telephone number34934344412119
    B.5.5Fax number34932531168
    B.5.6E-mailinvestigacion@mfar.net
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDinutuximab
    D.3.2Product code Ch14.18
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDINUTUXIMAB
    D.3.9.3Other descriptive nameDINUTUXIMAB
    D.3.9.4EV Substance CodeSUB130362
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Leukine
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi-Aventis
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLeukine
    D.3.2Product code PR2
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSARGRAMOSTIM
    D.3.9.1CAS number 123774-72-1
    D.3.9.2Current sponsor codePR2
    D.3.9.3Other descriptive namePR2
    D.3.9.4EV Substance CodeSUB10450MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg/ml microgram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Leukine
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi-Aventis
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLeukine
    D.3.2Product code PR2
    D.3.4Pharmaceutical form Powder and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSARGRAMOSTIM
    D.3.9.1CAS number 123774-72-1
    D.3.9.2Current sponsor codePR3
    D.3.9.3Other descriptive namePR3
    D.3.9.4EV Substance CodeSUB10450MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    High-risk neuroblastoma
    Neuroblastoma de alto riesgo
    E.1.1.1Medical condition in easily understood language
    High-risk neuroblastoma
    Neuroblastoma de alto riesgo
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10029260
    E.1.2Term Neuroblastoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate safety of the triple COG immunotherapy schema with the monoclonal antibody Dinutuximab + cytokines (GM-CSF and IL2) and isotretinoin (13-cis-retinoic acid, or RA) in patients with high-risk neuroblastoma who have achieved a CR or VGPR of the macroscopic disease in our institution.
    Evaluar la seguridad del esquema de inmunoterapia triple de COG con el anticuerpo monoclonal Dinutuximab + citoquina (GM-CSF y IL-2) e isotretionina (13 cis -ácido retinoico) en pacientes con neuroblastoma de alto riesgo que hayan alcanzado RC o muy buena respuesta parcial (VGPR) de la enfermedad macroscópica en nuestra institución.
    E.2.2Secondary objectives of the trial
    To assess response of minimal residual disease (MRD) of the anti-GD2 monoclonal antibody Dinutuximab combined with granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-2 in patients with high-risk neuroblastoma (NB). More precisely, to apply real-time quantitative RT-PCR to test the hypothesis that minimal residual
    disease content of BM after the first treatments with Dinutuximab/GM-CSF has significant prognostic impact on relapse-free survival.
    Determinar respuesta en términos de enfermedad residual mínima (MRD) del anticuerpo monoclonal Dinutuximab combinado con el factor estimulante de colonias de macrófagos (GM-CSF) e IL-2 en pacientes con neuroblastoma de alto riesgo. Mas precisamente, aplicar RT-PCR para probar la hipótesis que la enfermedad residual mínima contenida en la médula ósea después del primer tratamiento con Dinutuximab/GM-CSF tiene un impacto pronóstico significativo en la supervivencia liblre de recaída.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Diagnosis of neuroblastoma as defined by international criteria by histopathology or bone marrow metastases.
    2. Neuroblastoma, as defined by risk-related treatment guidelines and the International Neuroblastoma Staging System, stage 4 with (any age) or without (>18 months) MYCN-amplification, or MYCN-amplified neuroblastoma other than stage 1, or high-risk neuroblastoma defined based on the 3-gene molecular profile.
    Group 1 patients have neuroblastoma (as defined above) resistant to standard therapy, as evidenced by incomplete response in bone marrow, but no MIBG-avid soft tissue or bone tumor and no progressive disease.
    Group 2 patients have no evidence of measurable disease, i.e., are in CR/VGPR from neuroblastoma (as defined above).
    3. Signed informed consent indicating awareness of the investigational nature of this program.
    1. Diagnóstico de neuroblastoma según lo definido por los criterios internacionales por histopatología o metástasis de médula ósea.
    2. Neuroblastoma (según la definición de las directrices de tratamiento relacionado con el riesgo y el International Neuroblastoma Staging System), estadio 4 con amplificación MYCN (cualquier edad) o sin amplificación MYCN (> 18 meses), o neuroblastoma MYCN-amplificado distinto al estadio 1, o neuroblastoma de alto riesgo definido basado en el patrón de expresión de 3 genes.
    Grupo 1, los pacientes tienen neuroblastoma (como se define anteriormente) resistente a la terapia estándar, evidenciado por respuesta incompleta en médula ósea, pero no tumores MIBG-avid en tejido blando o hueso y sin enfermedad progresiva.
    Grupo 2, los pacientes no tienen evidencia de enfermedad medible, es decir, están en CR / VGPR de neuroblastoma (como se define anteriormente).
    3. Consentimiento firmado que indica el conocimiento de la naturaleza de investigación de este programa
    E.4Principal exclusion criteria
    1. Existing severe major organ dysfunction, i.e., renal., cardiac, hepatic, neurologic, pulmonary, or gastrointestinal toxicity >/= grade 3.
    2. Progressive disease or MIBG-avid soft tissue/bone tumor.
    3. Active life-threatening infection.
    4. Inability to comply with protocol requirements.
    5. Patient is elegible for SIOP HR-NB-01 protocol.
    1. Disfunción orgánica mayor o severa, es decir, renal, cardíaca, hepática, neurológica, pulmonar, gastrointestinal o toxicidad de grado >/= 3.
    2. Enfermedad progresiva o tumor MIBG-avid de tejido blando/hueso.
    3. Infecciones activas potencialmente mortales.
    4. Incapacidad para cumplir con los requisitos del protocolo.
    5. El paciente es elegible para el protocolo SIOP HR-NB-01.
    E.5 End points
    E.5.1Primary end point(s)
    Safety, toxicities: The safety and tolerability of the treatment will be determined by means of type, incidence, severity, timing, seriousness, and relatedness; of reported AEs, physical examinations, and laboratory tests. Toxicity will be graded and tabulated by the NCI-CTCAE v 4.0.
    Seguridad, toxicidad: La seguridad y tolerabilidad del tratamiento a estudio se evaluará por medio de la descripción de los efectos adversos que incluirá tipo, incidencia, severidad, momento de aparición, gravedad y relación con el tratamiento de los acontecimientos adversos reportados, exámenes físicos y determinaciones de laboratorio. La toxicidad será tabulada según la versión 4.0 del NCI-CTCAE.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every patient visit, during his/her participation in the clinical trial
    En cada visita del paciente durante su participación en el ensayo clínico.
    E.5.2Secondary end point(s)
    Rate of BM response for patients with detectable minimal residual disease in the BM after the first treatment with Dinutuximab/GM-CSF and relation with relapse-free survival. Relapsed-free survival: Defined as the time from the day of start of treatment to the first evidence of progression as defined by International Response Criteria (Brodeur et al., 1993) or death from any cause. If the patient does not have a documented date of progression or death, then PFS will be censored at the date of last adequate assessment.
    Tasa de respuesta BM para los pacientes con enfermedad residual mínima detectable en el BM después del primer tratamiento con Dinutuximab/GM-CSF y su relación con la supervivencia libre de recaída. Supervivencia libre de recaída: Se define como el tiempo desde el día de inicio del tratamiento hasta la primera evidencia de progresión según la definición de los criterios internacionales de respuesta (Brodeur et al, 1993) o muerte por cualquier causa. Si el paciente no tiene una fecha documentada de progresión o muerte, entonces PFS será censurado en la fecha de la última evaluación adecuada.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. BM studies at end of cycles 2 and 4 and after the 6th cycle of RA. Subsequently, BM studies are repeated in conjunction with MIBG or PET scan through 2 years in patients with history of BM or cortical bone involvement, but are repeated ~every 6 months in other patients (e.g., patients who were stage 4 by virtue of metastases in
    distant lymph nodes).
    2. CT or MRI of primary site approximately every 3 months through 1 year.
    3. 99mTc-MDP-bone approximately every 3 months while on study until normal.
    4. MIBG or PET scan approximately every 3 months through 2 years.
    1. Estudios de MO al final de los ciclos 2, 4 y después del sexto ciclo de RA. Posteriormente, los estudios MO se repitetirán en conjunto con MIBG o PET durante 2 años en pacientes con antecedentes de MO o afectación ósea cortical, pero se repiten ~ cada 6 meses en los demás casos (por ejemplo, los pacientes que se encontraban en estadio 4, en virtud de las metástasis en ganglios linfáticos distantes).
    2. TC o RM de sitio primario aproximadamente cada 3 meses, hasta 1 año.
    3. 99mTc-MDP-hueso aproximadamente cada 3 meses, durante el estudio hasta prueba de imagen normal.
    4. MIBG o PET aproximadamente cada 3 meses, por 2 años.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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 study will be considered closed from a normative point of view after data on primary and secondary variables are sufficiently prepared for its initial publication.
    El ensayo se considerará cerrado desde el punto normativo, una vez los datos de la variable primaria y secundaria estén lo suficientemente maduros para su publicación inicial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 10
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 10
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 10
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 10
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The highest incidence of neuroblastoma is in the first 2 years of life, 80% before 5 years of age, less than 2% over 18 years old. Subjects usually are incapable of giving consent personally in this study.
    La mayor incidencia de neuroblastoma se da en los 2 primeros años de vida, el 80% antes de los 5 años y menos del 2% en mayores de 18 años. Los sujetos habitualemente estarán incapacitados para dar el consentimiento personalmente en este estudio.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    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)
    Normal practise for the disease under study
    Práctica habitual en la enfermedad a estudio
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-05-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-04-10
    P. End of Trial
    P.End of Trial StatusOngoing
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