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    EudraCT Number:2012-004369-42
    Sponsor's Protocol Code Number:BAY73-4506/15983
    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:2013-10-01
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2012-004369-42
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-controlled Phase-III Study of Adjuvant Regorafenib Versus Placebo for Patients with Stage IV Colorectal Cancer After Curative Treatment of Liver Metastases
    Estudio Fase III, aleatorizado, doble ciego, controlado con placebo de regorafenib adyuvante frente a placebo en pacientes con cáncer colorrectal en estadio IV después de un tratamiento curativo de metástasis hepática.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This clinical study evaluates and compares the efficacy and safety of Regorafenib versus placebo in patients with coloreactal cancer after curative resection of liver metastasis and completion of all planned chemotherapy.
    Este estudio clínico evalúa y compara la eficacia y seguridad de Regorafenib versus placebo en pacientes con cáncer colorrectal después de la resección curativa de metástasis hepáticas y de completar toda la quimioterapia programada.
    A.3.2Name or abbreviated title of the trial where available
    Regorafenib as adjuvant therapy for resected liver metastases
    A.4.1Sponsor's protocol code numberBAY73-4506/15983
    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 SponsorBayer HealthCare AG
    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 supportBayer HealthCare AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer HealthCare AG
    B.5.2Functional name of contact pointBayer Clinical trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCTP Team / Ref: "EU CTR" Bayer Pharma AG
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    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. name Stivarga
    D. of the Marketing Authorisation holderBayer Pharma AG.
    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 nameRegorafenib
    D.3.2Product code Bay 73-4506
    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 INNRegorafenib
    D.3.9.1CAS number 755037-03-7
    D.3.9.2Current sponsor codeBay 73-4506
    D.3.9.3Other descriptive nameREGORAFENIB
    D.3.9.4EV Substance CodeSUB73090
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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) 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic Colorectal cancer
    Cáncer colorectal metastásico
    E.1.1.1Medical condition in easily understood language
    Cancer of the colon or rectum
    Cáncer de colon o recto.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10052362
    E.1.2Term Metastatic colorectal 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 evaluate and compare the efficacy and safety of regorafenib versus placebo in subjects with colorectal cancer (CRC) after curative resection of liver metastasis and completion of all planned chemotherapy.
    Evaluar y comparar la eficacia y la seguridad de regorafenib frente a placebo en pacientes con cáncer colorrectal (CCR) después de la resección curativa de metástasis hepáticas y de completar toda la quimioterapia programada
    E.2.2Secondary objectives of the trial
    Not Applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Eligible subjects must:

    1. Be male or female, and >=18 years of age

    2. Have a diagnosis of Stage IV CRC with metastases to the liver only and have undergone one of the following three treatment regimens:

    -A primary CRC lesion(s) in the colon and/or rectum and synchronous liver metastases, which were treated with surgery with curative intent for both primary and metastatic lesions and at least 3 months of neoadjuvant, adjuvant, or perioperative chemotherapy including a fluoropyrimidine and either oxaliplatin or irinotecan. Total chemotherapy administered, including that administered prior to and after liver resection, should not exceed 6 months.

    -A primary CRC lesion(s) in the colon and/or rectum, treated with surgery and at least 3 months of adjuvant chemotherapy with a) a fluoropyrimidine or b) a fluoropyrimidine and oxaliplatin or c) a fluoropyrimidine and irinotecan and > 6 months after completing treatment for primary CRC, developed liver metastases, which were treated with surgery with curative intent and a second course of chemotherapy lasting at least 3 months, including a fluoropyrimidine and either oxaliplatin or irinotecan. The second round of chemotherapy administered for the treatment of liver metastases should not exceed 6 months.

    -A primary CRC lesion(s) in the colon and/or rectum, treated with surgery and at least 3 months of chemotherapy, including a) a fluoropyrimidine, b) fluoropyrimidine and oxaliplatin, or c) fluoropyrimidine and irinotecan, and developed liver metastases ?6 months after completing treatment for primary CRC which were treated with surgery with curative intent. In this case, a second course of chemotherapy is not permitted unless initial adjuvant therapy consisted of fluoropyrimidine monotherapy. Subjects who received fluoropyrimidine alone must have received a second course of chemotherapy with fluoropyrimidine and either oxaliplatin and irinotecan. This second course of chemotherapy may be neoadjuvant, adjuvant, or perioperative. Radiofrequency ablation and chemoembolization are not permitted. Subjects undergoing a planned 2-stage resection of liver metastases may be enrolled into the study.

    3. Have tumor tissue (of primary tumor and liver metastases or at least one of the two) available for biomarker analysis (to be collected as soon as possible before or after randomization).

    4. Prior to randomization, have histological confirmation that all CRC lesions were adenocarcinoma. Subjects with CRC lesions of other histologic types, including mixed type with predominant adenocarcinoma, will not be eligible to be randomized to study treatment.

    5. Prior to randomization, have pathology-proven complete removal of all primary and liver metastatic CRC lesions. Subjects with positive margins will not be eligible for the study.

    6. Have had a computed tomography (CT) or magnetic resonance imaging (MRI) scan (chest, abdomen, pelvis and other suspected sites as applicable) to determine eligibility for randomization within 4 weeks prior to randomization (hereafter referred to as the "eligibility scan")

    7. Have absence of disease on the eligibility scan (CT/MRI) by investigator assessment and confirmed by central radiology review

    8. Have an Eastern Cooperative Oncology Group performance status of 0 or 1 within 14 days prior to the initiation of study treatment

    9. Have adequate bone marrow function, liver function, and renal function, as measured by laboratory assessments conducted within 7 days prior to the initiation of study treatment.

    10. Understand, be willing to give consent, and sign the written informed consent form (ICF) prior to undergoing any study-specific procedure.

    11. Be willing to give consent and sign the ICF for tumor tissue collection (primary tumor and liver metastases).

    12. Be willing to give consent and sign the ICF for the genetic testing unless precluded by local guidelines (eg, Independent Ethics Committee [IEC]/Institutional Review Board [IRB] or Regulatory Authority)

    13. If female and of childbearing potential, have a negative result on a pregnancy test performed a maximum of 7 days before initiation of study treatment.

    14. If female and of childbearing potential, or if male, agree to use adequate contraception (eg, abstinence, intrauterine device, oral contraceptive, or double-barrier method) based on the judgment of the investigator or a designated associate from the date on which the ICF is signed until 8 weeks after the last dose of study drug.
    Los pacientes a incluír deberán:
    1. Hombres y mujeres con edad mínima de 18 años.
    2. Diagnóstico de CCR en estadio IV con metástasis en el hígado solamente y que se han sometido a una de las 3 situaciones terapéuticas siguientes:
    -Lesiones primarias de CCR en colon y/o recto y metástasis hepáticas síncronas que se trataron con cirugía con intención curativa tanto para las lesiones primarias como para las metastásicas y al menos 3 meses de quimioterapia neoadyuvante, adyuvante o perioperatoria que incluye una fluoropirimidina y oxaliplatino o irinotecán. La quimioterapia total administrada, que incluye la administración antes y después de la resección hepática, no debe haber superado los 6 meses.
    -Lesiones de CCR primario en colon y/o recto, tratadas con cirugía y al menos 3 meses de quimioterapia adyuvante con a) una fluoropirimidina, b) una fluoropirimidina y oxaliplatino o c) una fluoropirimidina e irinotecán y > 6 meses después de completar el tratamiento del CCR primario, desarrollo de metástasis hepáticas que fueron tratadas con cirugía con intención curativa y un segundo ciclo de quimioterapia que duró al menos 3 meses, que incluyó una fluoropirimidina y oxaliplatino o irinotecán. La 2ª tanda de quimioterapia administrada para el tto de las metástasis hepáticas no debe haber superado los 6 meses.
    -Lesiones primarias de CCR en colon y/o recto tratadas con cirugía y al menos 3 meses de quimioterapia, incluidos a) una fluoropirimidina, b) fluoropirimidina y oxaliplatino o c) fluoropirimidina e irinotecán, y metástasis hepáticas desarrolladas >6 meses después de completar el tto del CCR primario, que fueron tratadas con cirugía con intención curativa. En este caso, no se permite administrar un segundo ciclo de quimioterapia salvo si el tratamiento adyuvante inicial consistió en monoterapia con una fluoropirimidina. Los pacientes que recibieron una fluoropirimidina sola tienen que haber recibido un segundo ciclo de quimioterapia con una fluoropirimidina y oxaliplatino o irinotecán.
    Este segundo ciclo de quimioterapia puede ser neoadyuvante, adyuvante o perioperatorio. No se permiten la ablación por radiofrecuencia y la quimioembolización. Se pueden incluir en el estudio pacientes sometidos a una resección planificada de las metástasis hepáticas en 2 etapas.
    3. Tejido tumoral disponible (del tumor primario y de las metástasis hepáticas, o al menos de uno de ellos) para el análisis de biomarcadores (debe obtenerse en cuanto sea posible antes o después de la aleatorización).
    4. Antes de la aleatorización, se tendrá la confirmación histológica de que todas las lesiones de CCR eran adenocarcinomas. Los pacientes con lesiones de CCR de otros tipos histológicos, incluido el tipo mixto con predominio de adenocarcinoma, no serán aptos para ser aleatorizados al tratamiento del estudio.
    5. Antes de la aleatorización, se habrán extirpado completamente todas las lesiones primarias y las metástasis hepáticas del CCR, confirmado por un estudio anatomopatológico. Los pacientes con márgenes positivos no son aptos para ser incluidos en este estudio.
    6. Tomografía computarizada (TC) o resonancia magnética (RM) (de tórax, abdomen, pelvis y otras localizaciones sospechosas cuando proceda) para determinar si el paciente es apto para la aleatorización en las 4 semanas anteriores a la aleatorización (denominado en lo sucesivo «exploración de elegibilidad»)
    7. Ausencia de enfermedad en la exploración de elegibilidad (TC/RM) según la evaluación del investigador y confirmada por la revisión radiológica centralizada
    8. Estado funcional del Eastern Cooperative Oncology Group de 0 o 1 en los 14 días anteriores al inicio del tratamiento del estudio
    9. Funciones medular ósea, hepática y renal adecuadas, evaluadas mediante las siguientes evaluaciones del laboratorio efectuadas en los 7 días previos al inicio del tratamiento del estudio
    10. El paciente entiende, está dispuesto a dar su consentimiento y firma el formulario de consentimiento informado (FCI) antes de someterse a ninguno de los procedimientos específicos del estudio.
    11. El paciente está dispuesto a dar su consentimiento informado y a firmar el FCI para obtención de tejido tumoral (tumor primario y metástasis hepáticas).
    12. El paciente está dispuesto a dar su consentimiento informado y a firmar el FCI para el estudio genético, salvo que lo impidan las leyes locales (p. ej.,
    el CEIC o las autoridades reguladoras)
    13. En el caso de mujeres que pueden quedarse embarazadas, resultado negativo en la prueba de embarazo realizada como máx 7 días antes de iniciar el tto del estudio.
    14. En el caso de mujeres que pueden quedarse embarazadas o de varones, aceptación de uso de anticonceptivos adecuados (p.ej. abstinencia sexual, dispositivo intrauterino, anticonceptivos orales o métodos de doble barrera) según criterio del investigador o del adjunto designado, desde fecha de firma del FCI hasta 8 semanas después de la última dosis del fármaco del estudio.
    E.4Principal exclusion criteria
    1. Are taking strong CYP3A4 inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St. John's Wort).
    2. Have used biologic response modifiers, such as granulocyte-colony stimulating factor, within 3 weeks of study entry
    3. Have had prior treatment with regorafenib or any other VEGFR-targeting kinase inhibitor.
    4. Have had anti-cancer treatment following liver resection that exceeded a duration of 6 months.
    5. Have been treated with biologics (eg, antibodies targeting VEGFR or EFGR) after liver resection unless the administration of the biologic started prior to liver resection and continued after liver resection only to complete a pre-specified number of cycles.
    6. Completed their last dose of chemotherapy or had their last cancer surgery more than 8 weeks, whichever came later, prior to randomisation.
    7. Have extra-hepatic metastatic disease. Suspicious lesions should be rigorously evaluated with other imaging techniques and/or biopsy to exclude extra-hepatic metastatic disease.
    8. Have been previously assigned to treatment during this study (subjects permanently withdrawn from study treatment will not be allowed to re-enter the study).
    9. Have had prior or concurrent cancer distinct in primary site or histology from CRC within 5 years prior to randomization EXCEPT for curatively treated cervical cancer in situ, nonmelanoma skin cancer, or superficial bladder tumors classified as noninvasive tumor (Ta), carcinoma in situ (Tis), or tumor invades lamina propria (T1).
    10. Have had systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and/or hormonal therapy within 4 weeks prior to initiation of study treatment.
    11. Have unresolved toxicity higher than National Cancer Institute-Common Terminology for Adverse Events version 4.0 (NCI-CTCAE v 4.0) Grade 1 attributed to any prior therapy/procedure, excluding alopecia and/or oxaliplatin-induced neurotoxicity <= Grade 2 and hemoglobin >= 9 g/dL as per inclusion criteria.
    12. Have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment.
    13. Are pregnant.
    14. Are breastfeeding.
    15. Are unable to swallow oral tablets (crushing of study treatment tablets is not allowed).
    16. Have congestive heart failure classified as New York Heart Association Class 2 or higher.
    17. Have had unstable angina (angina symptoms at rest) or new-onset angina <= 3 months prior to screening.
    18. Have had a myocardial infarction < 6 months prior to initiation of study treatment.
    19. Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin.
    20. Have uncontrolled hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90mm Hg) despite optimal medical management.
    21. Have pheochromocytoma.
    22. Have had arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within 6 months prior to the initiation of study treatment.
    23. Have an ongoing infection with severity of Grade 2 or above (NCI-CTCAE v 4.0).
    24. Have a known history of human immunodeficiency virus infection.
    25. Have either active hepatitis or chronic hepatitis B or C requiring treatment with antiviral therapy.
    26. Have a seizure disorder requiring medication.
    27. Have a history of organ allograft.
    28. Have evidence or history of any bleeding diathesis (including mild hemophilia), irrespective of severity.
    29. Have had a hemorrhage or a bleeding event >= Grade 3 (NCI-CTCAE v 4.0) within 4 weeks prior to the initiation of study treatment.
    30. Have a nonhealing wound, ulcer, or bone fracture.
    31. Have renal failure requiring hemodialysis or peritoneal dialysis.
    32. Have dehydration >= Grade 1 (NCI-CTCAE v 4.0).
    33. Have interstitial lung disease with ongoing signs and symptoms at the time informed consent is obtained.
    34. Have persistent proteinuria > 3.5 g/24 hours measured by urine protein-creatinine ratio from a random urine sample (>= Grade 3, NCI-CTCAE v 4.0).
    35. Have any other serious or unstable illness, or medical, psychological, or social condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures or may interfere with the subject's participation in the study or evaluation of the study results.
    36. Have a known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs.
    37. Have any malabsorption condition.
    38. Have a close affiliation with the investigational site (eg, be a close relative of the investigator) or be a dependent person (eg, be an employee or student working at the investigational site).
    1.Tomando inhibidores potentes del Citocromo P (CYP)3A4 (como claritromicina, indinavir, itraconazol, ketoconazol, nefazodona, nelfinavir, posaconazol, ritonavir, saquinavir, telitromicina o voriconazol) o inductores potentes del CYP3A4 (como carbamazepina, fenobarbital, fenitoína, rifampicina o hierba de S Juan)
    2.Han utilizado modificadores de la respuesta biológica, como G-CSF en las 3 semanas previas a la entrada en el estudio
    3.Han recibido tto previo con regorafenib o con cualquier otro inhibidor de cinasa dirigido al VEGFR
    4.Reciben tto antineoplásico después de resección hepática durante más de 6 meses.
    5.Han recibido tto con fármacos biológicos (p.ej. anticuerpos frente al VEGFR o al EGFR) después de resección hepática, salvo cuando la adm del producto biológico comenzara antes de la resección hepática y continuase después solo para completar nº de ciclos especificado con anterioridad
    6.Han completado su última dosis de quimioterapia o se han sometido a su última cirugía por el cáncer hace más de 8 semanas, lo que suceda más tarde, antes de la aleatorización
    7.Con enfermedad metastásica extrahepática. Deben evaluarse rigurosamente las lesiones sospechosas con otras técnicas de imagen y/o biopsias para excluir enfermedad metastásica extrahepática
    8.Asignados con anterioridad al tto durante este estudio (no se permitirá q los ptes en los q se haya retirado permanentemente el tto del estudio vuelvan a entrar)
    9.Han tenido cáncer anterior o concurrente distinto del CCR en lo que concierne a su lugar primario o a histología en los 5 años anteriores a la aleatorización, SALVO cáncer de cuello uterino in situ, de piel no melanoma o tumores de vejiga superficiales tratados de forma curativa y clasificados como tumor no invasivo (Ta), carcinoma in situ (Tis) o tumor que invade la lámina propia (T1)
    10.Han recibido tto antineoplásico sistémico, incluido el tto citotóxico, inhibidores de transducción de señales, inmunoterapia y/o tto hormonal en 4 semanas previas al inicio del tto del estudio
    11.Con efectos secundarios no resueltos > grado 1 según CTCAE del NCI v 4.0,atribuidos a cualquier tto o procedimiento previo, excepto alopecia y/o neurotoxicidad inducida por oxaliplatino de grado <= 2 y hemoglobina >= 9 g/dl según se indica en criterios de inclusión
    12.Sometidos a intervención quirúrgica mayor o biopsia abierta o han tenido lesión traumática grave en los 28 días previos al inicio del tto del estudio
    14.Dando el pecho
    15.No pueden tragar los comprimidos orales (no se permite triturar los del tto del estudio)
    16.Con insuficiencia cardiaca congestiva clasificada como >=clase 2 según la NYHA
    17.Han tenido angina inestable (síntomas de angina en reposo) o angina de nueva aparición >3 meses antes de la selección
    18.Han tenido un infarto de miocardio en 6 meses anteriores al inicio del tto del estudio
    19.Han tenido arritmias cardíacas con necesidad de tto antiarrítmico aparte de betabloqueantes o digoxina
    20.Con hipertensión no controlada (PAS>140 mmHg o PAD >90 mmHg) a pesar del tto médico óptimo.
    21.Con feocromocitoma
    22.Han tenido episodios embólicos o trombóticos venosos o arteriales como accidente cerebrovascular (incl.accidentes isquémicos transitorios), trombosis venosa profunda o embolia pulmonar en 6 meses anteriores al inicio del tto del estudio
    23.Con infección activa de grado 2 o mayor (CTCAE del NCI v 4.0)
    24.Con antecedentes conocidos de infección por virus de inmunodeficiencia humana
    25.Con hepatitis B o C activa o crónica q requiere tto antivírico
    26.Con trastornos convulsivos q requieren medicación
    27.Han recibido un aloinjerto
    28.Con signos o antecedentes de diátesis hemorrágica de cualquier tipo (incl.hemofilia leve) con independencia de la gravedad
    29.Han tenido hemorragia o episodio hemorrágico >= grado 3 (CTCAE del NCI, v 4.0) en 4 semanas anteriores al inicio del tto del estudio
    30.Con herida o úlcera sin cicatrizar o fractura ósea no consolidada
    31.Con insuficiencia renal q requiere hemodiálisis o diálisis peritoneal
    32.Con deshidratación >= grado 1 (CTCAE del NCI v 4.0)
    33.Con enfermedad pulmonar intersticial con signos y síntomas q continúan en momento de obtener el FCI
    34.Con proteinuria persistente > 3,5 g/24 horas, medida por un cociente proteínas/creatinina en orina en muestra de orina aleatoria (>= grado 3, CTCAE del NCI v 4.0).
    35.Con otra enfermedad grave o inestable o un problema médico, psicológico o social q pudiera poner en riesgo la seguridad del pte y/o su cumplimiento con procedimientos del estudio o interferir con la participación del pte o con la evaluación de los resultados del estudio
    36.Con hipersensibilidad conocida a cualquier fármaco del tto del estudio, clases de los fármacos del estudio o excipientes de la formulación de fármacos del estudio
    37.Con problema de malabsorción
    38.Con filiación estrecha (p.ej., familiar cercano a investigador) o personas dependientes del centro (p. ej. empleado/ estudiante)
    E.5 End points
    E.5.1Primary end point(s)
    Disease-free survival (DFS)
    Supervivencia sin enfermedad (SSE)
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint, disease-free survival (DFS) as assessed by the investigator, will be measured by CT/MRI scans obtained at screening and every 3 months during the first 3 years of the study, then 6-monthly for a further year, then yearly until disease recurrence.
    El criterio de valoración principal del estudio, la SSE evaluada por el investigador, se medirá mediante exploraciones de TC/RM obtenidas en el momento de la selección y cada 3 meses durante los primeros 3 años del estudio, después cada 6 meses durante un año más y, por último, anualmente hasta la recurrencia de la enfermedad.
    E.5.2Secondary end point(s)
    Overall survival
    Supervivencia global
    E.5.2.1Timepoint(s) of evaluation of this end point
    All subjects will be followed until death (unless consent for Overall Survival follow-up is withdrawn).
    Todos los pacientes serán seguidos hasta el fallecimiento ( a menos que retiren su consentimiento para seguimiento de 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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) 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 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 Yes
    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 EEA29
    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
    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
    última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months10
    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: 375
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 375
    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 state62
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 271
    F.4.2.2In the whole clinical trial 750
    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)
    Following completion of treatment or withdrawal for any other reason, all subjects will have a 30-day Safety Follow-up visit. Subjects who finish treatment or withdraw from study treatment for any reason other than death or disease recurrence will enter Active Follow-up.
    En 30 días, tras la finalización del tratamiento o retirada por cualquier otro motivo, todos los pacientes tendrán una visita de seguimiento. Los sujetos que finalizen el tratamiento o se retiren de tratamiento del estudio por cualquier motivo que no sea la muerte o recurrencia de la enfermedad entrarán en seguimiento activo.
    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 Decision2013-11-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-11-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-08-29
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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