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    EudraCT Number:2014-002117-28
    Sponsor's Protocol Code Number:ACE-LY-004
    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:2015-06-15
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-002117-28
    A.3Full title of the trial
    An Open-label, Phase 2 Study of ACP-196 in Subjects
    with Mantle Cell Lymphoma
    Estudio de fase II abierto sobre ACP-196 en sujetos con linfoma de células del manto
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Trial to See the Effects of ACP-196 (the test drug) in Patients who have Mantle Cell Lymphoma
    Estudio para ver los efectos de ACP-196 ( el fármaco del estudio) en pacientes con linfoma de células del manto.
    A.4.1Sponsor's protocol code numberACE-LY-004
    A.5.4Other Identifiers
    Name:IND NumberNumber:118717
    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 SponsorAcerta Pharma BV
    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 supportAcerta Pharma BV
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcerta Pharma BV
    B.5.2Functional name of contact pointACE-LY-004 Clincial Team
    B.5.3 Address:
    B.5.3.1Street AddressMolenstraat 110
    B.5.3.2Town/ cityOss
    B.5.3.3Post code5342 CC
    B.5.4Telephone number+34900838465
    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.3.2Product code ACP-196
    D.3.4Pharmaceutical form Capsule
    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 INNNot yet assigned
    D.3.9.3Other descriptive nameACP-196
    D.3.9.4EV Substance CodeSUB166233
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Mantle Cell Lymphoma
    Linfoma de Células del Manto
    E.1.1.1Medical condition in easily understood language
    lymphoma (nodes of the neck, chest, armpit or groin) cancer
    Linfoma (nódulos del cuello, pecho, axila o ingle)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level HLT
    E.1.2Classification code 10026798
    E.1.2Term Mantle cell lymphomas
    E.1.2System Organ Class 100000004851
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the activity of ACP-196 in subjects with relapsed or refractory MCL as measured primarily by response rate. In addition, activity of ACP-169 will be assessed by duration of response, progression-free survival, and overall survival.
    Determinar la actividad de ACP-196 en sujetos con recaída de un LCM o un LCM refractario determinada principalmente mediante la tasa de respuesta. Además, la actividad de ACP-196 se evaluará en función de la duración de la respuesta, la supervivencia sin progresión y la supervivencia general.
    E.2.2Secondary objectives of the trial
    ? To characterize the safety profile of ACP-196
    ? To characterize the pharmacokinetic (PK) profile of ACP-196
    ? To evaluate the PD effects of ACP-196
    Caracterizar el perfil de seguridad de ACP-196
    Caracterizar el perfil FC de ACP-196
    Evaluar los efectos FD de ACP-196
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men and women ? 18 years of age.
    2. Pathologically confirmed MCL, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1.
    3. Disease has relapsed after or been refractory to ? 1 prior therapy for MCL and now requires further treatment.
    4. Documented failure to achieve at least PR with, or documented disease progression after, the most recent treatment regimen.
    5. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of ? 1 lesion that measures ? 2.0 cm in the longest dimension and ? 1.0 cm in the longest perpendicular dimension as assessed by computed tomography [CT] scan).
    6. At least 1, but no more than 5, prior treatment regimens for MCL (Note: Subjects having received ? 2 cycles of prior treatment with bortezomib, either as a single agent or as part of a combination therapy regimen, will be considered to be bortezomib-exposed.)
    7. Eastern Cooperative Oncology Group (ECOG) performance status of ? 2.
    8. Agreement to use acceptable methods of contraception during the study and for 30 days after the last dose of study drugs if sexually active and able to bear or beget children.
    9. Agreement to refrain from sperm donation during the study and for 30 days after the last dose of study drug.
    10. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
    11. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations).
    1.Hombres y mujeres ? 18 años de edad.
    2.LCM confirmado anatomopatológicamente, con documentación de linfocitos B monoclonales con translocación cromosómica t(11;14)(q13;q32) o que sobreexpresan cliclina D1.
    3.Recaída de la enfermedad después de ? 1 tratamiento previo o refractoriedad a ? 1 tratamiento previo para la LCM y necesidad actual de tratamiento adicional.
    4.Fracaso documentado para lograr al menos una respuesta parcial (RP), o progresión de la enfermedad documentada con posterioridad, con la pauta terapéutica más reciente.
    5.Presencia de linfadenopatía mensurable por métodos radiológicos o neoplasia linfoide extraganglionar (definida por la presencia de ? 1 lesión que mide ? 2,0 cm en su dimensión más grande y ? 1,0 cm en la dimensión perpendicular más grande según la tomografía axial computarizada [TAC]).
    6.Al menos 1, pero no más de 5 pautas terapéuticas anteriores para la LCM (Nota: Se considerarán sujetos con exposición a bortezomib aquellos que hayan recibido ? 2 ciclos de tratamiento previo con bortezomib, bien como fármaco único o como parte de un tratamiento combinado).
    7.Estado general ? 2 del Grupo oncológico cooperativo del este (ECOG).
    8.Aceptar el uso de métodos anticonceptivos satisfactorios durante el estudio y 30 días después de la última dosis del fármaco del estudio cuando el sujeto es sexualmente activo y es capaz de engendrar o tener hijos.
    9.Aceptar no donar esperma durante el estudio y en los 30 días después de haber recibido la última dosis del fármaco del estudio.
    10.Desear y ser capaz de participar en todas las evaluaciones y procedimientos de este protocolo del estudio, entre ellas tragar las cápsulas sin dificultad.
    11.Capacidad de comprender el objetivo y los riesgos del estudio y de otorgar el consentimiento informado firmado y fechado y la autorización para usar información sanitaria protegida (de acuerdo con las normativas nacionales y locales sobre la privacidad de los sujetos).
    E.4Principal exclusion criteria
    1. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for ? 2 years or which will not limit survival to < 2 years. Note: these cases must be discussed with the medical monitor.
    2. A life-threatening illness, medical condition or organ system dysfunction which, in the investigator?s opinion, could compromise the subject?s safety, interfere with the absorption or metabolism of ACP-196, or put the study outcomes at undue risk.
    3. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or QTc > 480 msec.
    4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
    5. Any immunotherapy within 4 weeks of first dose of study drug.
    6. The time from the last dose of the most recent chemotherapy or experimental therapy to the first dose of study drug is < 5 times the half-life of the previously administered agent(s).
    7. Prior exposure to a BCR inhibitor (eg, Btk inhibitors, phosphoinositide-3 kinase (PI3K), or Syk inhibitors) or BCL-2 inhibitor (eg, ABT-199).
    8. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids for treatment of MCL or other conditions. Note: Subjects may use topical or inhaled corticosteroids or low-dose steroids (? 10 mg of prednisone or equivalent per day) as therapy for comorbid conditions. During study participation, subjects may also receive systemic or enteric corticosteroids as needed for treatment-emergent comorbid conditions.
    9. Grade ? 2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.
    10. Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic infection.
    11. Major surgery within 4 weeks before first dose of study drug.
    12. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
    13. Known history of a bleeding diathesis (eg, hemophilia, von Willebrand disease)
    14. History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug.
    15. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonist (eg, phenprocoumon) within 28 days of first dose of study drug.
    16. Requires treatment with long-acting proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, exlansoprazole, rabeprazole, or pantoprazole).
    17. ANC < 0.75 x 109/L or platelet count < 50 x 109/L; for subjects with disease involvement in the bone marrow, ANC < 0.50 x 109/L or platelet count < 30 x 109/L.
    18. Creatinine > 2.5 x institutional upper limit of normal (ULN); total bilirubin > 2.5 x ULN ; and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3.0 x ULN.
    19. Breastfeeding or pregnant.
    20. Concurrent participation in another therapeutic clinical trial.
    1.Neoplasia previa, excepto un cáncer cutáneo de células escamosas o de células basales tratado correctamente, cáncer cervical in situ u otro cáncer en el que el sujeto haya estado ? 2 años sin la enfermedad o cuyo límite de supervivencia no sea < 2 años. Nota: Estos casos deben ser analizados con el supervisor médico.
    2.Cualquier enfermedad, trastorno médico o disfunción de un sistema orgánico potencialmente mortal que, en opinión del investigador, podría poner en peligro la seguridad del sujeto, interferir con la absorción o el metabolismo de ACP-196 o suponer un riesgo excesivo para los resultados del estudio.
    3.Enfermedad cardiovascular clínicamente significativa como arritmia no controlada o sintomática, insuficiencia cardíaca congestiva, infarto de miocardio en los 6 meses anteriores a la selección, o cualquier cardiopatía de clase 3 o 4 según la definición de la Clasificación funcional de la New York Heart Association.
    4.Síndrome de mala absorción, enfermedad que afecta significativamente a la función gastrointestinal o resección del estómago o del intestino delgado, derivación gástrica, enfermedad intestinal inflamatoria sintomática u obstrucción intestinal parcial o completa.
    5.Cualquier inmunoterapia en las 4 semanas siguientes a la primera dosis del fármaco del estudio.
    6.El periodo de tiempo desde la última dosis de la quimioterapia o del tratamiento experimental más reciente hasta la primera dosis del fármaco del estudio es < 5 veces la semivida del fármaco o fármacos administrados previamente.
    7.Exposición previa a un inhibidor de BCR (p. ej., inhibidores de Btk o inhibidores de fosfoinositida-3 cinasa [PI3K]).
    8.Tratamiento inmunosupresor en curso, incluidos los corticosteroides sistémicos o entéricos para el tratamiento de la LCM u otros trastornos. Nota:
    Los sujetos pueden utilizar corticosteroides tópicos o inhalados o dosis bajas de esteroides (? 10 mg de prednisona o equivalente al día) como tratamiento de trastornos comórbidos. Durante la participación en el estudio, los sujetos pueden recibir también corticosteroides sistémicos o entéricos cuando sea necesario como tratamiento de trastornos comórbidos surgidos durante el tratamiento.
    9. Toxicidad de grado ? 2 (diferente a alopecia) que se mantiene desde un tratamiento antineoplásico previo, incluida radiación.
    10. Antecedentes conocidos de virus de inmunodeficiencia humana (VIH) o una infección activa por el virus de hepatitis B (VHB), el virus de hepatitis C (VHC) o cualquier infección sistémica activa no controlada.
    11. Cirugía mayor en las 4 semanas anteriores a la primera dosis de ACP-196.
    12.Anemia hemolítica autoinmunitaria no controlada o púrpura trombocitopénica idiopática.
    Historia conocida de una diastesis hemorrágica (como hemofilia o enfermedad de Von Willebrand)
    14.Antecedentes de ictus o de hemorragia intracraneal en los 6 meses anteriores a la primera dosis de ACP-196.
    15. Necesidad de anticoagulación con warfarina o con un antagonista de la vitamina K.
    16. Requiere tratamiento con inhibidores de la bomba de protones de acción prolongada (como omeprazol, esomeprazol, lanzoprazol, exlansoprazol, rabeprazol o pantoprazol)
    17.Recuento absoluto de neutrófilos (RAN) < 0,5 x 109/l o recuento de plaquetas < 25 x 109/l, a menos que sea consecuencia de la afectación de la médula ósea por la enfermedad.
    18. Creatinina > 2,5 x límite superior de la normalidad (LSN) del centro; bilirrubina total > 2,5 x LSN (a menos que el sujeto tenga una enfermedad de Gilbert); y > 2,5 x LSN de aspartato aminotransferasa (AST) o alanina aminotransferasa (ALT), excepto cuando el incremento se relaciona con la enfermedad.
    19. Lactancia o embarazo.
    20.Participación simultánea en otro ensayo clínico terapéutico.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is the overall response rate (ORR) defined as a subject achieving either a partial remission (PR) or complete remission (CR) response according to the Lugano Classification for non-Hodgkin lymphoma as assessed by investigators.
    El criterio de valoración principal del estudio es la tasa de respuesta general (TRG), definida como un sujeto que logra una RP o una RC según la clasificación del LNH de Lugano según la evaluación efectuada por los investigadores.
    E.5.1.1Timepoint(s) of evaluation of this end point
    @ 30 days after stopping study treatment
    Sobre 30 días despues de suspender el tratamiento del estudio
    E.5.2Secondary end point(s)
    ? duration of response (DOR)
    ? progression-free survival (PFS)
    ? overall survival (OS)

    ? frequency, severity, and relatedness of adverse events
    ? frequency of adverse events requiring discontinuation of study drug or dose reductions
    ? effect of ACP-196 on peripheral T/B/NK cell counts
    ? effect of ACP-196 on serum immunoglobulin levels

    ? plasma pharmacokinetics of ACP-196

    Patient Reported Outcomes (PRO):
    ? health-related quality of life

    ? plasma pharmacokinetics of ACP-196

    Patient Reported Outcomes (PRO):
    ? health-related quality of life
    ? Duración de la respuesta (DR)
    ? Supervivencia sin progresión (SSP)
    ? Supervivencia general (SG)
    ? Frecuencia, gravedad y relación de los acontecimientos adversos (AA)
    ? Frecuencia de AA que obligan a la interrupción del fármaco del estudio o a reducciones de la dosis
    ? Efecto de ACP-196 sobre los recuentos de linfocitos T/B/linfocito citolítico natural
    ? Efecto de ACP-196 sobre las concentraciones séricas de inmunoglobulinas
    ? Farmacocinética plasmática de ACP-196
    Resultados comunicados por el paciente (RCP):
    ? Calidad de vida relacionada con la salud
    E.5.2.1Timepoint(s) of evaluation of this end point
    @ 30 days after stopping study treatment
    Sobre 30 días despues de suspender el tratamiento del estudio
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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. 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.8.2.4Number 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Czech Republic
    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
    LVLS (at the end of the follow up visit after last dose)
    Última visita del último paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    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: 59
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 58
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 117
    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 defined
    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 Decision2015-07-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-08
    P. End of Trial
    P.End of Trial StatusOngoing
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