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    Summary
    EudraCT Number:2010-021037-32
    Sponsor's Protocol Code Number:I4T-MC-JVBB
    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:2010-11-25
    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 number2010-021037-32
    A.3Full title of the trial
    A Randomized, Double-Blind, Multicenter Phase 3 Study of Irinotecan, Folinic Acid, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab or Placebo in Patients With Metastatic Colorectal Carcinoma Progressive During or Following First-Line Combination Therapy With Bevacizumab, Oxaliplatin, and a Fluoropyrimidine
    Estudio de fase 3, multicéntrico, aleatorizado y doble ciego con irinotecán, ácido folínico y 5-fluorouracilo (FOLFIRI) más ramucirumab o placebo en pacientes con carcinoma colorrectal metastásico que presentan progresión durante o después de un tratamiento combinado de primera línea con bevacizumab, oxaliplatino y una fluoropirimidina
    A.3.2Name or abbreviated title of the trial where available
    RAISE
    A.4.1Sponsor's protocol code numberI4T-MC-JVBB
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLilly 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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameRamucirumab DP
    D.3.2Product code IMC-1121B (LY3009806)
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 947 687-13-0
    D.3.9.2Current sponsor codeIMC-1121B (LY3009806)
    D.3.9.3Other descriptive namerecombinant human IgG1 monoclonal antibody (MAb) targeted to VEGFR-2
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typerecombinant monoclonal antibody Anticuerpo monoclonal recombinante
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 CAMPTO 40 mg/2 ml concentrado para solución para perfusión
    D.2.1.1.2Name of the Marketing Authorisation holderPFIZER, S.A.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNIRINOTECAN HIDROCLORURO TRIHIDRATO
    D.3.9.3Other descriptive nameIRINOTECAN HIDROCLORURO TRIHIDRATO
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typeProducto Quimioterapico
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Calciumfolinat
    D.2.1.1.2Name of the Marketing Authorisation holderHospira Deutschland GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNFOLINIC ACID
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Neofluor
    D.2.1.1.2Name of the Marketing Authorisation holderNeoCorp AG
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 name5-Fluorouracil
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INN5-FLUOROURACIL
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 Campto 100 mg/5 ml, concentrado para solución para perfusión
    D.2.1.1.2Name of the Marketing Authorisation holderPFIZER, S.A.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNIRINOTECAN HIDROCLORURO TRIHIDRATO
    D.3.9.3Other descriptive nameIRINOTECAN HIDROCLORURO TRIHIDRATO
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typeMedicamento Quimioterapico
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Cancer Colorectal Metastasico
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10010036
    E.1.2Term Colorectal carcinoma
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    El objetivo principal de este estudio consiste en comparar la supervivencia global (SG) en pacientes con carcinoma colorrectal (CCR) metastásico cuando reciben tratamiento con FOLFIRI en combinación con placebo frente a FOLFIRI en combinación con ramucirumab.
    E.2.2Secondary objectives of the trial
    Los objetivos secundarios consisten en comparar el tratamiento con FOLFIRI más placebo con el tratamiento con FOLFIRI más ramucirumab en cuanto a:
    supervivencia sin progresión (SSP)
    tasa de respuestas objetivas (TRO)
    medidas de resultados comunicados por los pacientes (RCP) (cuestionarios QLQ-C30 de la European Organisation for Research and Treatment of Cancer [EORTC] y EuroQol EQ 5D)
    perfil de seguridad
    evaluación de la asociación entre biomarcadores y evolución clínica

    Además, los objetivos secundarios comprenden:
    evaluación de los anticuerpos contra ramucirumab (inmunogenicidad)
    evaluación de la concentración sérica de ramucirumab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    [1]El paciente presenta un CCR confirmado por métodos histológicos o citológicos (los pacientes podrán participar con independencia del estado de mutación en KRAS).
    [2] El paciente presenta un CCR metastásico confirmado.
    [3] El estado de mutación en KRAS del paciente se conoce antes de la aleatorización.
    [4]El paciente ha recibido tratamiento combinado de primera línea con bevacizumab, oxaliplatino y una fluoropirimidina por enfermedad metastásica y:
    a. ha presentado progresión radiológica de la enfermedad durante el tratamiento de primera línea, o
    b. ha presentado progresión radiológica de la enfermedad en el plazo de 6 meses tras la última dosis del tratamiento de primera línea, o
    c. ha suspendido parte o todo el tratamiento de primera línea debido a toxicidad y ha presentado progresión radiológica de la enfermedad en el plazo de 6 meses tras la última dosis del tratamiento de primera línea.
    Obsérvese que un paciente tendrá que haber recibido un mínimo de 2 dosis de bevacizumab como parte de un régimen de primera línea que contenga quimioterapia.
    [5]El paciente presenta enfermedad metastásica que no es susceptible de resección potencialmente curativa en opinión del investigador.
    [6]El paciente ha recibido no más de 2 regímenes previos de quimioterapia sistémica en cualquier contexto (únicamente se permite un régimen previo por enfermedad metastásica). En los pacientes con cáncer rectal, el tratamiento neoadyuvante y adyuvante secuenciales contarán como tratamiento sistémico único.
    [7]El paciente presenta enfermedad mensurable o no mensurable según los Criterios de evaluación de la respuesta en tumores sólidos, versión 1.1 (RECIST v. 1.1).
    [8]El paciente presenta resolución a un grado 1, según los Criterios terminológicos comunes para acontecimientos adversos del National Cancer Institute, versión 4.02 (CTCAE del NCI v. 4.02), de todos los efectos tóxicos con importancia clínica de la quimioterapia, cirugía, radioterapia u hormonoterapia previa, con la excepción de neuropatía periférica, que tendrá que haberse resuelto a un grado 2 y salvo que se indique lo contrario en los criterios de participación.
    [9]El paciente presenta un estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 ó 1.
    [10]El paciente presenta una función hematológica adecuada según lo definido por un recuento absoluto de neutrófilos (RAN) 1,5 x 103/µl (1,5 x 109/l), una hemoglobina 9 g/dl (5,58 mmol/l) y un recuento de plaquetas 100 x 103/µl (100 x 109/l).
    [11]El paciente presenta una función de coagulación adecuada según lo definido por un cociente normalizado internacional (INR) 1,5 y un tiempo de tromboplastina parcial (TTP) 1,5 veces el límite superior de la normalidad (LSN) en caso de no recibir tratamiento anticoagulante. Los pacientes que estén en tratamiento con anticoagulantes en dosis plenas deberán estar recibiendo una dosis estable (duración mínima de 14 días) de un anticoagulante oral o una heparina bajo peso molecular y, en caso de recibir warfarina, tener un INR 3 y no presentar hemorragia activa con importancia clínica (definida como la que aparece en los 14 días anteriores a la aleatorización) ni procesos patológicos que conlleven un riesgo elevado de hemorragia.
    [12]El paciente presenta una función hepática adecuada según lo definido por una bilirrubina total dentro de los límites normales y una aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) 3,0 veces el LSN o 5,0 veces el LSN si la elevación de las aminotransferasas es consecuencia de metástasis hepáticas.
    [13]El paciente presenta una función renal adecuada según lo definido por un aclaramiento de creatinina > 50 ml/min (0,835 ml/s) medido a partir de una recogida de orina de 24 horas o calculado mediante una ecuación que cuenta con el respaldo de directrices institucionales locales.
    [14]Las proteínas en orina del paciente son 1+ en una tira reactiva o análisis de orina sistemático; si las proteínas en orina son 2+, se recogerá una muestra de orina de 24 horas, en la que tendrán que identificarse < 1.000 mg de proteínas en 24 horas para permitir la participación en el estudio.
    [15]El paciente, sea varón o mujer, se compromete a emplear un método anticonceptivo fiable durante el período del estudio y durante 12 semanas después de la última dosis del tratamiento del estudio.
    [16]Las mujeres en edad fértil deberán tener una prueba de embarazo negativa en el momento de inclusión, basándose en una prueba de embarazo en suero realizada en los 7 días anteriores a la aleatorización.
    [17]El paciente muestra disposición a cumplir el calendario y los procedimientos del protocolo.
    [18]El paciente es capaz de otorgar su consentimiento informado por escrito.
    [19]El paciente acepta donar una muestra histórica de tejido de CCR para efectuar una evaluación de biomarcadores.
    [20]El paciente tiene una edad mínima de 18 años.
    E.4Principal exclusion criteria
    [21]El paciente ha recibido bevacizumab en los 28 días anteriores a la aleatorización.
    [22]El paciente ha recibido quimioterapia en los 21 días anteriores a la aleatorización.
    [23]El paciente ha recibido radioterapia de campo amplio (pélvica en dosis plenas) en los 28 días anteriores a la aleatorización.
    [24]El paciente ha recibido cualquier tratamiento en investigación en los 28 días anteriores a la aleatorización.
    [25]El paciente ha recibido cualquier tratamiento sistémico previo, aparte de una combinación de bevacizumab, oxaliplatino y una fluoropirimidina, como tratamiento de primera línea del CCR metastásico.
    [26]El paciente tiene antecedentes de trastornos hemorrágicos o trombóticos hereditarios o adquiridos no controlados.
    [27]El paciente presenta, en opinión del investigador, una enfermedad intercurrente no controlada, como, por ejemplo, hipertensión arterial no controlada, insuficiencia cardíaca congestiva sintomática, angina de pecho inestable, arritmia cardíaca sintomática o mal controlada, enfermedad psiquiátrica/situaciones sociales o cualquier otro trastorno médico grave no controlado.
    [28]El paciente ha presentado episodios trombóticos o tromboembólicos arteriales, como, por ejemplo, infarto de miocardio, accidente isquémico transitorio o accidente cerebrovascular, en los 12 meses anteriores a la aleatorización.
    [29]El paciente presenta afectación leptomeníngea o metástasis cerebrales conocidas o una compresión medular no controlada.
    [30]El paciente presenta una infección en curso o activa con necesidad de tratamiento antibiótico, antimicótico o antiviral parenteral.
    [31]El paciente presenta una infección conocida por el virus de la inmunodeficiencia humana o una enfermedad relacionada con el síndrome de inmunodeficiencia adquirida.
    [32]El paciente ha recibido un órgano o trasplante autólogo o alogénico con anterioridad.
    [33]El paciente se ha sometido a cirugía mayor en los 28 días anteriores a la aleatorización o a la colocación de un dispositivo subcutáneo de acceso venoso en los 7 días anteriores a la aleatorización.
    [34]El paciente ha sufrido una herida, úlcera o fractura ósea grave que no cicatriza o consolida en los 28 días anteriores a la aleatorización.
    [35]El paciente tiene programada o prevista una intervención de cirugía mayor que se practicará durante el transcurso del ensayo.
    [36]La paciente está embarazada (confirmado mediante un análisis de gonadotropina coriónica humana beta [&#946; HCG] en suero en los 7 días anteriores a la aleatorización) o se encuentra en período de lactancia.
    [37]El paciente presenta una neoplasia maligna activa coexistente distinta de un cáncer de piel no melanomatoso debidamente tratado, un carcinoma in situ de cuello uterino tratado con intención curativa o otros carcinomas no infiltrantes o neoplasias in situ. Un paciente con antecedentes de una neoplasia maligna podrá participar, siempre que se haya mantenido sin enfermedad durante > 3 años.
    [38]El paciente tiene antecedentes de enfermedad inflamatoria intestinal o enfermedad de Crohn con necesidad de intervención médica (medicamentos inmunomoduladores o inmunodepresores o cirugía) en los 12 meses anteriores a la aleatorización.
    [39]El paciente presenta una obstrucción intestinal aguda o subaguda o antecedentes de diarrea crónica que, en opinión del investigador, se considere de importancia clínica.
    [40]El paciente ha presentado un episodio hemorrágico de grado 3 o mayor en los 3 meses anteriores a la aleatorización.
    [41]El paciente presenta una enfermedad ulcerosa péptica asociada a un episodio hemorrágico o una diverticulitis activa conocida.
    [42]El paciente ha presentado alguno de los procesos siguientes durante el tratamiento de primera línea con un régimen que contenía bevacizumab: episodio trombótico o tromboembólico arterial, hipertensión arterial de grado 4, proteinuria de grado 4, episodio hemorrágico de grado 3-4 o perforación intestinal.
    [43]El paciente tiene antecedentes conocidos o datos clínicos de Síndrome de Gilbert o se sabe que posee uno de los genotipos siguientes: UGT1A1*6/*6, UGT1A1*28/*28 o UGT1A1*6/*28.
    [44]El paciente presenta alergia conocida a alguno de los componentes del tratamiento del estudio, incluido cualquiera de los componentes utilizados en la preparación de ramucirumab, u otra contraindicación para recibir los tratamientos del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    supervivencia global
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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 Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA69
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    Ultima visita del ultimo 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 months0
    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 months2
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 state65
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 475
    F.4.2.2In the whole clinical trial 1050
    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)
    Despues de la terminacion del tratamiento del estudio el paciente sera tratado segun las indicaciones del investigador o medico de referencia
    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 Decision2011-02-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-02-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-08-01
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