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    Summary
    EudraCT Number:2018-002998-21
    Sponsor's Protocol Code Number:CLEE011O12301C
    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:2019-01-18
    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 number2018-002998-21
    A.3Full title of the trial
    A phase III, multicenter, randomized, open-label trial toevaluate efficacy and safety of ribociclib with endocrine therapy as an adjuvant treatment in patients with hormone receptor-positive, HER2-negative, early breast cancer (New Adjuvant TriAl with Ribociclib [LEE011]: NATALEE)
    Ensayo clínico fase III, multicéntrico, aleatorizado y abierto, para evaluar la eficacia y seguridad de ribociclib con terapia endocrina, como tratamiento adyuvante en pacientes con cáncer de mama precoz, receptores hormonales positivos, HER2 negativo (nuevo ensayo clínico en adyuvancia con ribociclib - [LEE011]: NATALEE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase III multi-center, randomized, open-label trial to evaluate efficacy and safety of ribociclib with
    endocrine therapy as adjuvant treatment in patients with HR+/HER2- Early Breast Cancer.
    Ensayo clínico fase III, multicéntrico, aleatorizado y abierto, para evaluar la eficacia y seguridad de ribociclib con terapia endocrina, como tratamiento adyuvante en pacientes con cáncer de mama precoz con receptores hormonales positivos, HER2 negativo.
    A.4.1Sponsor's protocol code numberCLEE011O12301C
    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 SponsorNovartis Farmacéutica S.A.
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica S.A.
    B.5.2Functional name of contact pointTMO
    B.5.3 Address:
    B.5.3.1Street AddressGran Vía de les Corts Catalanes 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number+34900353036
    B.5.5Fax number+34932479903
    B.5.6E-maileecc.novartis@novartis.com
    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 Yes
    D.2.1.1.1Trade name Kisqali
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameribociclib
    D.3.2Product code LEE011
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRIBOCICLIB
    D.3.9.1CAS number 1374639-75-4
    D.3.9.2Current sponsor codeLEE011
    D.3.9.4EV Substance CodeSUB180246
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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
    Hormone receptor-positive, HER2-negative, early breast cancer.
    Cáncer de mama precoz con receptores hormonales positivos, HER2 negativo.
    E.1.1.1Medical condition in easily understood language
    Early breast cancer.
    Cáncer de mama precoz.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10006203
    E.1.2Term Breast cancer stage unspecified
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10070575
    E.1.2Term Estrogen receptor positive breast cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare iDFS for ribociclib + ET versus ET in patients with HRpositive, HER2-negative, EBC.
    Comparar la supervivencia libre enfermedad invasiva (SLEi ) de ribociclib + terapia endocrina (TE) comparado a terapia endocrina (TE) en pacientes con cáncer de mama precoz (CMP), receptores hormonales (RH) positivos, HER2 negativo.
    E.2.2Secondary objectives of the trial
    1. To evaluate the two treatment arms with respect to recurrence-free survival (RFS).
    2. To evaluate the two treatment arms with respect to distant diseasefree survival (DDFS).
    3. To evaluate the two treatment arms with respect to OS.
    4. To evaluate patient reported outcomes (PRO) for health-related quality of life (QoL) in the two
    treatment arms.
    5. To characterize the PK of ribociclib when given in combination with NSAI (and goserelin if applicable).
    1. Evaluar en los dos brazos de tratamiento la supervivencia libre de recaída (SLR).
    2. Evaluar en los dos brazos de tratamiento la supervivencia libre de enfermedad a distancia (SLED).
    3. Evaluar en los dos brazos de tratamiento la supervivencia global (SG).
    4. Evaluar los resultados comunicados por el paciente (PROs, de las siglas en inglés, Patient Reported Outcomes) relacionados con la salud a través de los cuestionarios de calidad de vida (CdV) en los dos brazos de tratamiento.
    5. Caracterizar la farmacocinética (FC) de ribociclib al administrarse en combinación con un IANE (y goserelina, si procede).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patient is ≥ 18 years-old at the time of PICF signature.
    - Patient is female with known menopausal status at the time of PICF signature or initiation of adjuvant ET (whichever occurs earlier), or male.
    - Patient with histologically confirmed unilateral primary invasive adenocarcinoma of the breast with a date of initial cytologic or histologic diagnosis within 18 months prior to randomization.
    - Patient has breast cancer that is positive for ER and/or PgR.
    - Patient has HER2-negative breast cancer.
    - Patient has available archival tumor tissue from the surgical specimen.
    - Patient after surgical resection where tumor was removed completely, with the final surgical specimen microscopic margins free from tumor, and who belongs to one of the following categories (anatomic stage group II or III).
    - If indicated, patient has completed adjuvant and/or neoadjuvant chemotherapy according to the
    institutional guidelines.
    - If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines.
    - Patient has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET for 5 years.
    - Paciente ≥ 18 años en el momento de firmar la Hoja de información y consentimiento informado del paciente (HICIP).
    - Mujer con menopausia conocida en el momento de firmar la HICIP o de iniciar la TE adyuvante (lo que ocurra en primer lugar), o varón.
    - Paciente con adenocarcinoma mamario primario infiltrante y unilateral, confirmado histológicamente, con fecha de diagnóstico citológico o histológico inicial dentro de los 18 meses anteriores a la aleatorización.
    - Paciente con cáncer de mama positivo para RE y/o RPg.
    - Paciente con cáncer de mama HER2 negativo.
    - Paciente con tejido tumoral archivado, procedente de una pieza quirúrgica.
    - Paciente sometida a resección quirúrgica en la que el tumor fue resecado completamente, con márgenes microscópicos de la pieza quirúrgica final libres de tumor, y perteneciente a una de las siguientes categorías (estadio anatómico II o III).
    - Si estaba indicada, el paciente tiene que haber finalizado la quimioterapia adyuvante y/o neoadyuvante de acuerdo con los protocolos del centro.
    - Si estaba indicada, el paciente tiene que haber finalizado la radioterapia adyuvante de acuerdo con los protocolos del centro.
    - El paciente no presenta ninguna contraindicación para la TE adyuvante del ensayo y se ha programado que reciba TE durante 5 años.
    E.4Principal exclusion criteria
    - Patient has received any CDK4/6 inhibitor.
    - Patient has received prior treatment with tamoxifen, raloxifene or AIs for reduction in risk (“chemoprevention”) of breast cancer and/or treatment for osteoporosis within the last 2 years prior to PICF signature.
    - Patient has received prior treatment with anthracyclines at cumulative doses of 450 mg/m² or more for doxorubicin, or 900 mg/m² or more for epirubicin.
    - Patient with a known hypersensitivity to any of the excipients of ribociclib and/or ET.
    - Patient with distant metastases of breast cancer beyond regional lymph nodes (stage IV according to AJCC 8th edition) and/or evidence of recurrence after curative surgery.
    - Patient is concurrently using other anti-neoplastic therapy with the exception of adjuvant ET.
    - Patient has had major surgery, chemotherapy or radiotherapy within 14 days prior to randomization.
    - Patient has not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies.
    - Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was
    completed within 2 years before PICF signature.
    - Patient has known HIV infection, Hepatitis B or C infection.
    - Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
    - Patient is currently receiving any of the following substances within 7 days before randomization:
    Concomitant medications, herbal supplements, and/or fruits that are known as strong inhibitors or inducers of CYP3A4/5 or Medications that have a narrow therapeutic window and are predominantly
    metabolized through CYP3A4/5.
    - Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting trial treatment.
    - Patient has impairment of GI function or GI disease that may significantly alter the absorption of the oral trial treatments.
    - Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the
    Investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol.
    - Patient participated in another interventional study and received treatment with an investigational product (or used an investigational device) within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer.
    - Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial.

    Additional exclusion criteria as per full protocol may apply.
    - Paciente que ha recibido algún inhibidor de CDK4/6.
    - Paciente que ha recibido tratamiento previo con tamoxifeno, raloxifeno o un IA para la reducción del riesgo de cáncer de mama (“quimioprevención”) y/o tratamiento de la osteoporosis dentro de los 2 años anteriores a la firma de la HICIP.
    - Paciente que ha recibido tratamiento previo con antraciclinas, con dosis acumuladas de 450 mg/m² o más de doxorrubicina, o de 900 mg/m² o más de epirrubicina.
    - Paciente con hipersensibilidad conocida a cualquiera de los excipientes de ribociclib y/o de la TE.
    - Paciente con metástasis a distancia del cáncer de mama, más allá de los ganglios linfáticos regionales (estadio IV según la clasificación del AJCC, 8ª edición) y/o evidencia de recaída después de una intervención quirúrgica con intención curativa.
    - Paciente que recibe simultáneamente otro tratamiento antineoplásico, con la excepción de la TE adyuvante.
    - Paciente sometido a una cirugía mayor, quimioterapia o radioterapia dentro de los 14 días anteriores a la aleatorización.
    - Paciente no recuperado de las toxicidades agudas clínicas o analíticas relacionadas con tratamientos antineoplásicos previos.
    - Paciente con neoplasia maligna infiltrante concurrente o neoplasia maligna infiltrante anterior cuyo tratamiento haya finalizado en los 2 años anteriores a la firma de la HICIP.
    - Paciente con antecedentes conocidos de infección por el virus de la inmunodeficiencia humana (VIH), hepatitis B (VHB) o de la hepatitis C (VHC).
    - Patología cardiaca no controlada y clínicamente significativa y/o alteración de la repolarización cardiaca.
    - El paciente está recibiendo actualmente alguna de las siguientes sustancias, en los 7 días anteriores a la aleatorización: Medicación concomitante, suplementos de plantas medicinales y/o frutas o sus zumos, conocidos por ser potentes inhibidores o inductores del CYP3A4/5 o Medicamentos con un estrecho margen terapéutico que se metabolizan predominantemente a través del CYP3A4/5.
    - Paciente que actualmente recibe o ha recibido corticoides sistémicos ≤ 2 semanas antes de iniciar el tratamiento del ensayo.
    - Paciente con deterioro de la función gastrointestinal (GI) o una enfermedad digestiva que pueda alterar de forma importante la absorción de los tratamientos orales del ensayo.
    - Paciente que presenta cualquier otra patología médica grave y/o no controlada concurrente que, en opinión del investigador, podría causar riesgos inaceptables para la seguridad, contraindica la participación del paciente en el ensayo clínico, compromete el cumplimiento del protocolo.
    - Paciente que haya participado en otro estudio intervencionista y haya recibido tratamiento con un producto en investigación (o usado un dispositivo en investigación) dentro de los 30 días anteriores a la aleatorización o dentro de 5 semividas del producto en investigación, lo que sea más prolongado.
    - Mujer embarazada o en periodo de lactancia, o mujer que planea quedarse embarazada o amamantar a un bebé durante el ensayo.

    Pueden aplicar criterios de exclusión adicionales según el protocolo completo.
    E.5 End points
    E.5.1Primary end point(s)
    iDFS using STEEP criteria, as assessed by Investigator.
    Supervivencia libre enfermedad invasiva (SLEi) utilizando los criterios STEEP (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials), según la evaluación del Investigador.
    E.5.1.1Timepoint(s) of evaluation of this end point
    3.5 years
    3,5 años
    E.5.2Secondary end point(s)
    - Recurrence free survival (RFS) using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials).
    - Distant disease free survival (DDFS) using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials).
    - Overall survival (OS).
    - Change from baseline in the physical functioning subscale score and global health status/Quality of life scale score as assessed by EORTC QLQ-C30.
    - PK parameters such as Cmax, Tmax, and AUC 0- 24h for ribociclib.
    - Supervivencia libre de recaída (SLR) utilizando los criterios STEEP (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials).
    - Supervivencia libre de enfermedad a distancia (SLED) utilizando los criterios STEEP (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials).
    - Supervivencia global (SG).
    - Cambio respecto al momento basal en la puntuación de la subescala de funcionamiento físico y en la puntuación de la escala de situación global de salud/CdV, evaluado mediante el cuestionario EORTC QLQ-C30.
    - Parámetros Farmacocinéticos de ribociclib, como Cmax, Tmax, y AUC 0-24h.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - 3.5 years.
    - 3.5 years.
    - 7.5 years.
    - 3.5 years.
    - 3.5 years.
    - 3,5 años.
    - 3,5 años.
    - 7,5 años.
    - 3,5 años.
    - 3,5 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 Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    - Quality of life (QoL) and patient reported outcomes (PRO).
    - Calidad de vida (CdV) y resultados comunicados por el paciente (PROs, de las siglas en inglés, Patient Reported Outcomes).
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned35
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA201
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Canada
    China
    France
    Germany
    Hungary
    Ireland
    Italy
    Korea, Republic of
    Peru
    Poland
    Romania
    Russian Federation
    Spain
    Taiwan
    United Kingdom
    United States
    E.8.7Trial 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
    End of trial will be declared when 60 months + 30 days have elapsed from the date the last patient has been randomized.
    El final del ensayo se declarará cuando hayan transcurrido 60 meses + 30 días a partir de la fecha en que el último paciente haya sido asignado al azar.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial days4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2000
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2000
    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 Yes
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state443
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1764
    F.4.2.2In the whole clinical trial 4000
    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)
    Endocrine therapy or any other anti-cancer treatment according to investigator's clinical judgement.
    Terapia endocrina o cualquier otro tratamiento contra el cáncer según el criterio clínico del investigador.
    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 Decision2019-02-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-06
    P. End of Trial
    P.End of Trial StatusOngoing
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