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    Summary
    EudraCT Number:2013-000536-10
    Sponsor's Protocol Code Number:00103311
    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:2013-10-18
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2013-000536-10
    A.3Full title of the trial
    A Phase 3, Randomized, Open Label Study Investigating the Efficacy of the BiTE® Antibody Blinatumomab Versus Standard of Care Chemotherapy in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (TOWER Study)
    Estudio de fase 3, aleatorizado y abierto que investiga la eficacia del anticuerpo BiTE® blinatumomab en comparación con el tratamiento estándar de quimioterapia en sujetos adultos con leucemia linfoblástica aguda (LLA) de precursores B recidivante/refractaria (estudio TOWER)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical Phase 3 Study to evaluate the comparative efficacy of the bispecific antibody blinatumomab versus standard of care chemotherapy, in adult subjects with Acute Lymphoblastic Leukemia that did not respond to previous therapy or that relapsed after initially successful previous therapy
    Estudio fase 3 que investiga la eficacia del anticuerpo biespecífico blinatumomab en comparación con el tratamiento estándar de quimioterapia, en sujetos adultos con Leucemia Linfoblástica Aguda que no respondieron a tratamientos previos o que presentaron recaída después de un tratamiento previo inicial con éxito.
    A.3.2Name or abbreviated title of the trial where available
    TOWER Study
    estudio TOWER
    A.4.1Sponsor's protocol code number00103311
    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 SponsorAmgen Inc.
    B.1.3.4CountryUnited States
    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 supportAmgen Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen (EUROPE) GmbH
    B.5.2Functional name of contact pointIHQ medical Info-Clinical Trials
    B.5.3 Address:
    B.5.3.1Street AddressDammstrasse 23, P.O. Box 1557
    B.5.3.2Town/ cityZug
    B.5.3.3Post codeCH-6300
    B.5.3.4CountrySwitzerland
    B.5.6E-mailMedinfoInternational@amgen.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/09/650
    D.3 Description of the IMP
    D.3.1Product nameBlinatumomab
    D.3.2Product code AMG 103, MT103
    D.3.4Pharmaceutical form Powder for 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 INNBlinatumomab
    D.3.9.1CAS number 853426-35-4
    D.3.9.2Current sponsor codeAMG 103
    D.3.9.3Other descriptive nameBLINATUMOMAB
    D.3.9.4EV Substance CodeSUB35403
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30.3
    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) Yes
    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
    Adult patients with relapsed and/or refractory B-precursor Acute lymphoblastic leukaemia
    Pacientes adultos con leucemia linfoblástica aguda de precursores B recidivante/refractaria
    E.1.1.1Medical condition in easily understood language
    Adult patients with Acute lymphoblastic leukaemia - a cancer of the blood and marrow - which did not completely respond to treatment or has relapsed after first responding to therapy
    Pacientes adultos con leucemia linfoblástica aguda - un cáncer de sangre y médula - que no respondieron completamente al tratamiento o presentan recaída después de recibir el primer tratamiento.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10000845
    E.1.2Term Acute lymphoblastic leukemia
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10063625
    E.1.2Term Acute lymphoblastic leukemia recurrent
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    evaluate the effect of blinatumomab on overall survival (OS) when compared to standard of care (SOC) chemotherapy
    Evaluar el efecto de blinatumomab en la supervivencia global (SG) en comparación con el tratamiento estándar (SOC) de quimioterapia.
    E.2.2Secondary objectives of the trial
    - evaluate hematological response induced by blinatumomab when compared to SOC chemotherapy
    - evaluate event free survival induced by blinatumomab when compared to SOC chemotherapy
    - evaluate minimal residual disease (MRD) remissions induced by blinatumomab when compared to SOC chemotherapy
    - estimate the effect of blinatumomab on patient reported outcomes, global health status/quality of life (QoL) using the EORTC QLQ-C30
    - evaluate the incidence of allogeneic hematopoietic stem cell transplantation (alloHSCT) and 100-day mortality following HSCT in blinatumomab treated subjects when compared to SOC chemotherapy
    - evaluate the safety of blinatumomab when compared to SOC chemotherapy
    Exploratory:
    - evaluate blinatumomab exposure-response relationships for efficacy and safety
    - assess presence of ALL symptoms as measured by Acute Lymphoblastic Leukemia Symptom Scale (ALLSS)
    - assess the potential for mutations in the tumor DNA to predict resistance to blinatumomab treatment
    -Evaluar respuesta hematológica inducida por blinatumomab en comparación con SOC de quimioterapia.
    -Evaluar SLA inducida por blinatumomab en comparación con SOC de quimioterapia.
    -Evaluar remisiones de ERM inducidas por blinatumomab en comparación con SOC de quimioterapia.
    -Estimar efecto de blinatumomab en resultados notificados por el paciente, el estado de salud global/QoL mediante el EORTC QLQ-C30.
    -Evaluar incidencia de trasplante alogénico de células progenitoras hematopoyéticas (TCPHalog) y mortalidad a los 100 días tras TCPH en sujetos con blinatumomab en comparación con SOC de quimioterapia.
    -Evaluar seguridad de blinatumomab en comparación con SOC de quimioterapia.
    -Evaluar relaciones entre exposición a blinatumomab y respuesta eficacia y seguridad.
    -Evaluar la presencia de los síntomas de la LLA medidos por la escala de síntomas de la leucemia linfoblástica aguda (ALLSS).
    -mutaciones en el ADN del tumor para predecir la resistencia al tratamiento con blinatumomab.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects with Philadelphia negative B-precursor ALL, with any of the following:
    - refractory to primary induction therapy or refractory to salvage therapy,
    - in untreated first relapse with first remission duration <12 months
    - in untreated second or greater relapse
    - or relapse at any time after allogeneic HSCT
    2. Subject has received intensive combination chemotherapy for the treatment of ALL for initial treatment or subsequent salvage therapy.
    3. Greater than 5% blasts in the bone marrow
    4. Eastern Cooperative Oncology Group (ECOG) performance status ? 2
    5. Age ? 18 years at the time of informed consent
    6. Subject has provided informed consent or subjects legally acceptable representative has provided informed consent when the subject has any kind of condition that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent.
    - Sujetos con LLA de precursores B con cromosoma Filadelfia negativo y cualquiera de las características siguientes:
    1. refractarios al tratamiento de inducción principal o refractarios al tratamiento de rescate
    2. en primera recaída no tratada con una duración de la primera remisión de < 12 meses
    3. en segunda recaída no tratada o posterior
    4.o recidiva en cualquier momento después de un TCPH alogénico.
    -El sujeto ha recibido quimioterapia combinada intensiva para el tratamiento de LLA durante el tratamiento inicial o el tratamiento de rescate posterior.
    -Más del 5% de blastos en la médula ósea.
    -Estado funcional ECOG (Eastern Cooperative Oncology Group) ? 2.
    - Edad ? 18 años en el momento del consentimiento informado.
    -El sujeto ha proporcionado el consentimiento informado o el representante legal autorizado del sujeto ha proporcionado el consentimiento informado cuando el sujeto sufre cualquier tipo de afección que, según la opinión del investigador, puede comprometer su capacidad para proporcionar el consentimiento informado por escrito.
    E.4Principal exclusion criteria
    1. History of malignancy other than ALL within 5 years prior to start of protocol-specified therapy with the exception of:
    - Malignancy treated with curative intent and with no known active disease present for 5 years before enrollment and felt to be at low risk for recurrence by the treating physician
    - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    - Adequately treated cervical carcinoma in situ without evidence of disease
    - Adequately treated breast ductal carcinoma in situ without evidence of disease
    - Prostatic intraepithelial neoplasia without evidence of prostate cancer.
    2. Diagnosis of Burkitt´s Leukemia according to WHO classification
    3. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinsons disease, cerebellar disease, organic brain syndrome, or psychosis with the exception of history of CNS leukemia that is controlled with intrathecal therapy
    4. Active ALL in the CNS (confirmed by CSF analysis) or testes
    5. Isolated extramedullary disease
    6. Current autoimmune disease or history of autoimmune disease with potential CNS involvement
    7. Autologous HSCT within 6 weeks before the start of protocol-specified therapy
    8. Allogeneic HSCT within 12 weeks before the start of protocol-specified therapy
    9. Any active acute Graft-versus-Host Disease (GvHD), grade 2-4 according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
    10. Any systemic therapy against GvHD within 2 weeks before start of protocol-specified therapy
    11. Known exclusion criteria to investigator choice of SOC chemotherapy (as per product insert).
    12. Cancer chemotherapy within 2 weeks before start of protocol-specified therapy (intrathecal chemotherapy and dexamethasone are allowed until start of protocol-specified therapy). In addition, any subject whose organ toxicity (excluding hematologic) from prior ALL treatment has not resolved to no more than CTCAE grade 1
    13. Radiotherapy within 2 weeks before the start of protocol-specified therapy
    14. Immunotherapy (e.g., rituximab) within 4 weeks before start of protocol-specified therapy
    15. Subject received prior anti-CD19 therapy
    4.2.16 Abnormal screening laboratory values as defined below:
    - AST (SGOT) and/or ALT (SGPT) and/or ALP ? 5 x upper limit of normal (ULN)
    - Total bilirubin (TBL) ? 1.5 x ULN (unless related to Gilbert´s or Meulengracht disease)
    - Creatinine ? 1.5 ULN or Creatinine clearance < 60 ml/min (calculated)
    17. Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HBsAg positive) or hepatitis C virus (anti-HCV positive)
    18. Subject is pregnant or breast feeding, or might become pregnant within 3 months after the last dose of protocol-specified therapy
    19. Woman of childbearing potential and is not willing to use 2 highly effective methods of contraception while receiving protocol-specified therapy and for an additional 3 months after the last dose of protocol-specified therapy.
    20. Male who has a female partner of childbearing potential, and is not willing to use 2 highly effective forms of contraception while receiving protocol-specified therapy and for at least an additional 3 months after the last dose of protocol-specified therapy.
    21. Male who has a pregnant partner, and is not willing to use a condom during sexual activity while receiving protocol-specified therapy and for 3 months after the last dose of protocol-specified therapy
    22. Currently receiving treatment in another investigational device or drug study or less than 30 days since ending treatment on another investigational device or drug study(s). Thirty days is calculated from Day 1 of protocol-specified therapy.
    23. Other investigational procedures while participating in this study are excluded.
    24. Subject has known sensitivity to immunoglobulins or any of the products or components to be administered during dosing.
    25. Subject previously has randomized into this study or previous treatment with blinatumomab.
    26. Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject and Investigator?s knowledge.
    27. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the Investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
    * Antecedentes de otros tumores malignos distintos de la LLA 5 años anteriores al inicio del tto requerido por el protocolo con la excepción de:
    - Tumor maligno tratado con intención curativa y sin enfermedad activa confirmada presente durante 5 años previos a la inclusión y que el médico tratante considere de bajo riesgo de recurrencia.
    - Cáncer de piel no melanomatoso o lentigo maligno tratados adecuadamente sin evidencia de enfermedad.
    - Carcinoma cervicouterino in situ tratado adecuadamente sin evidencia de enfermedad.
    -Carcinoma ductal de mama in situ tratado adecuadamente sin evidencia de enfermedad.
    -Neoplasia intraepitelial prostática sin evidencia de cáncer de próstata.
    *Diagnóstico de leucemia de Burkitt según la clasificación de la OMS.
    *Antecedentes o presencia de una patología del SNC clínicamente relevante como epilepsia, convulsiones en la infancia o en la edad adulta, paresia, afasia, infarto cerebral, lesiones cerebrales graves, demencia, enfermedad de Parkinson, enfermedad del cerebelo, síndrome orgánico cerebral o psicosis.
    Con la excepción de antecedentes de leucemia en el SNC controlada con tratamiento intratecal.
    *LLA activa en el SNC o en los testículos.
    *Enfermedad extramedular aislada.
    *Enfermedad autoinmune actual o antecedentes de enfermedad autoinmune con posible afectación del SNC.
    *TCPH autólogo durante las 6 semanas anteriores al inicio del tratamiento especificado en el protocolo.
    *TCPH alogénico durante las 12s anteriores al inicio del tto especificado en protocolo.
    *Cualquier EICH aguda activa de grado 2-4 según criterios de Glicksberg o EICH crónica activa que requiere tto sistémico.
    *Cualquier tto sistémico contra la EICH durante las 2s anteriores al inicio del tto especificado en el protocolo
    *Criterios de exclusión conocidos para recibir SOC de quimioterapia elegido por el IP.
    *Quimioterapia contra el cáncer durante las 2s anteriores al inicio de tto especificado en protocolo. cualquier sujeto cuya toxicidad orgánica (excluida la hematológica), causada por el tto previo de la LLA, no se ha resuelto hasta no más de grado1 de los CTCAE.
    *Radioterapia durante las 2S anteriores al inicio del tto especificado en protocolo.
    *Inmunoterapia durante las 4s anteriores al inicio del tto especificado en protocolo.
    *sujeto recibió anteriormente tto anti-CD19.
    *Valores analíticos anormales en la selección:
    - AST y/o ALT y/o FA ? 5 x LSN.
    - BiT ? 1,5 x LSN (a no ser que esté relacionada con la enfermedad de Gilbert o Meulengracht).
    - Creatinina ? 1,5 LSN o aclaramiento de creatinina < 60 mL/min.
    *Infección conocida por virus deVIH o HBsAg positivo o anti-VHC positivo.
    *Mujer embarazada o en período de lactancia, o que planee quedarse embarazada en los 3m después de la última dosis del tto especificado en el protocolo.
    *Mujer en edad fértil y que no quiera utilizar 2 métodos anticonceptivos altamente eficaces mientras recibe el tratamiento especificado por el protocolo y durante 3 meses adicionales más tras la última dosis del tratamiento especificado en el protocolo.
    *Hombre que tiene como pareja a una mujer en edad fértil y que no quiera utilizar 2 métodos anticonceptivos altamente eficaces mientras recibe el tratamiento especificado en el protocolo y como mínimo, durante 3 meses más tras la última dosis del tratamiento especificado en el protocolo.
    *Hombre que tiene una pareja embarazada y que no quiere utilizar un preservativo durante el acto sexual mientras recibe el tratamiento especificado en el protocolo y durante 3 meses tras la última dosis del tratamiento especificado en el protocolo.
    *Estar recibiendo tratamiento en otro estudio de un fármaco o dispositivo en investigación o haber transcurrido menos de 30 días desde el fin del tratamiento en otro estudio de un fármaco o dispositivo en investigación. Los treinta días se calculan a partir del día 1 del tratamiento especificado en el protocolo.
    *Queda excluido cualquier otro procedimiento de investigación mientras se participe en este estudio.
    *El sujeto presenta una sensibilidad conocida a las inmunoglobulinas o a alguno de los productos o componentes que se administrarán durante la dosificación.
    *El sujeto se ha aleatorizado previamente en este estudio o ha recibido previamente tratamiento con blinatumomab.
    *Según informan el sujeto y el investigador, es posible que el sujeto no esté disponible para completar todas las visitas o procedimientos del estudio requeridos por el protocolo, incluidas las visitas de seguimiento, y/o cumplir todos los procedimientos del estudio.
    *Antecedentes o signos de cualquier otro trastorno, afección o enfermedad clínicamente significativa (a excepción de las descritas anteriormente) que, en opinión del investigador o del médico de Amgen, si se consultan, puedan suponer un riesgo para la seguridad del sujeto o interferir en la evaluación, los procedimientos o la finalización del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival
    supervivencia global
    E.5.1.1Timepoint(s) of evaluation of this end point
    Assessment when the 330th death is reported or 12 months after the last subject is randomized, whichever occurs first. If 330 deaths have
    not been observed 12 months after the last subject is randomized then the primary analysis will occur when at least 300 deaths have been reported in the database (300 deaths provides approximately 80% unconditional power).
    se observe 330 muertes notificadas ó 12 meses después de haberse aleatorizado al último sujeto, lo que ocurra primero.si no se han observado 330 muertes 12 meses después de que se haya aleatorizado al último sujeto, el análisis principal se realizará cuando, como mínimo, se hayan observado 300 muertes (300 muertes proporciona aproximadamente un 80% de potencia incondicional).
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Endpoints (in order of hierarchical testing)
    1. CR within 12 weeks of treatment initiation
    2. CR/CRh*/CRi within 12 weeks of treatment initiation
    3. Event Free Survival (EFS)
    Secondary Efficacy Endpoints
    4. Duration of CR
    5. Duration of CR/CRh*/CRi
    6. MRD remission (defined as MRD level below 10-4 by PCR or flow cytometry)
    7. Time to a 10 point decrease from baseline in global health status and QoL scale using EORTC QLQ-C30, or EFS event
    8. AlloHSCT with or without blinatumomab treatment
    Secondary Safety Endpoints
    9. Incidence of adverse events
    10. 100-day mortality after alloHSCT
    11. Incidence of anti-blinatumomab antibody formation
    12. Changes in select vital sign and laboratory parameters
    Exploratory Endpoints
    13. Blinatumomab steady state concentration (Css)
    14. ALLSS score at measured time points
    15. Investigation for mutations in the tumor DNA to predict resistance to blinatumomab treatment
    Variables de eficacia secundarias clave (por orden jerárquico de pruebas)
    - RC durante las 12 semanas posteriores al inicio del tratamiento.
    - RC/RCh*/RCi durante las 12 semanas posteriores al inicio del tratamiento.
    - Supervivencia libre de acontecimientos (SLA).
    - Duración de la RC.
    - Duración de la RC/RCh*/RCi.
    - Remisión de la ERM (definida como el nivel de ERM por debajo de 10-4 determinado mediante RCP o citometría de flujo).
    - Tiempo hasta una reducción de 10 puntos desde el nivel basal en el estado de salud global y en la escala de calidad de vida mediante el EORTC QLQ-C30, o un acontecimiento de SLA.
    - TCPHalog con o sin tratamiento con blinatumomab.
    - Incidencia de acontecimientos adversos.
    - Mortalidad a los 100 días tras un TCPHalog.
    - Incidencia de formación de anticuerpos anti-blinatumomab.
    - Cambios en ciertas constantes vitales y parámetros analíticos.
    - Concentración de blinatumomab en estado de equilibrio (Css)
    - Puntuación de la ALLSS en puntos temporales medidos.
    - Investigación de las mutaciones en el ADN del tumor para predecir la resistencia al tratamiento con blinatumomab.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1+2: after 12 weeks; samples are taken at the end of cycles 1 and 2
    3: at the time of relapse, death or EOS
    4+5+15: throughout the study; samples are taken at the end of each cycle, at the safety follow-up visit and every 3 months during long-term follow-up
    6: at the end of cycles 1 and 2
    7+12+14: troughout treatment and at the safety follow-up visit
    8+9: throughout the study
    10: 100 days after alloHSCT
    11: before first dose, after cycle 2 and at the safety follow-up visit
    13: day 1 and 15 of cycle 1
    1+2: después de 12 semanas; las muestras se toman al final del ciclo 1 y 2.
    3: en el momento de la recaída, fallecimiento o final de ensayo.
    4+5+15: a lo largo del estudio; las muestras se toman al final de cada ciclo, en la visita de seguimiento de seguridad cada 3 meses durante el seguimiento a largo plazo.
    6: al final del ciclo 1 y 2.
    7+12+14: a lo largo del tratamiento y de la visita de seguimiento de seguridad.
    8+9: a lo largo del estudio
    10: 100 días después de TCPH
    11: antes de la primera dosis, después del ciclo 2 y de la visita de seguimiento de seguridad.
    13: día 1 y 15 del ciclo 1.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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) 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 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) 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA71
    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
    Australia
    Austria
    Belgium
    Bulgaria
    Canada
    Czech Republic
    France
    Germany
    Greece
    Ireland
    Israel
    Italy
    Korea, Republic of
    Mexico
    Poland
    Russian Federation
    Spain
    Taiwan
    Turkey
    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 is defined as the time when the last subject is assessed or receives an intervention for the purposes of final data collection for the study.
    Se define como el momento en que el último sujeto se evalúa o recibe una intervención para la evaluación en el estudio, incluidas las evaluaciones de supervivencia.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    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: 308
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 92
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    If the subject has any kind of condition that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent, the subject's legally acceptable representative can provide written informed consent.
    Si el paciente presenta cualquier condición que, en la opinión del investigador, podría comprometer la habilidad del paciente para dar su consentimiento informado, el representarte legal puede firmar el consentimiento informado.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 253
    F.4.2.2In the whole clinical trial 400
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-11-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-11-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-03-14
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