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    The EU Clinical Trials Register currently displays   43974   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    EudraCT Number:2011-006194-26
    Sponsor's Protocol Code Number:EC11-185
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2012-02-13
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2011-006194-26
    A.3Full title of the trial
    A phase IV, multicenter, randomized, double-blind, placebo-controlled study of efficacy and safety of Sorafenib in patients with hepatocellular carcinoma after radiological progression
    Estudio fase IV, multicéntrico, aleatorizado, doble-ciego, controlado frente a placebo, para evaluar la eficacia y seguridad de Sorafenib en pacientes con carcinoma hepatocelular avanzado con progresión radiológica.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase IV study of efficacy and safety of Sorafenib in patients with hepatocellular carcinoma after radiological progression
    Estudio fase IV para evaluar la eficacia y seguridad de Sorafenib en pacientes con carcinoma hepatocelular avanzado con progresión radiológica.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberEC11-185
    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.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMINISTERIO DE SANIDAD, POLITICA SOCIAL E IGUALDAD
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.2Functional name of contact pointCLINICAL UNIT OF DIGESTIVE SYSTEM
    B.5.3 Address:
    B.5.3.1Street AddressAV/ MENENDEZ PIDAL
    B.5.3.2Town/ cityCORDOBA
    B.5.3.3Post code14004
    B.5.4Telephone number34957010328
    B.5.5Fax number34957736014
    D. IMP Identification
    D.IMP: 1
    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. name Nexavar
    D. of the Marketing Authorisation holderBayer Pharma AG
    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.3.1Product nameSorafenib
    D.3.4Pharmaceutical form Capsule, hard
    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.3.9.1CAS number 475207-59-1
    D.3.9.2Current sponsor code475207-59-1
    D.3.9.3Other descriptive nameSORAFENIB TOSILATE
    D.3.9.4EV Substance CodeSUB22347
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. 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 Yes
    D. medicinal product typemultikinase inhibitor
    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 placeboCapsule, hard
    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
    Advanced stage hepatocellular carcinoma (stage C of BCLC classification)
    Carcinoma hepatocelular avanzado (estadio C de la clasificación BCLC)
    E.1.1.1Medical condition in easily understood language
    Hepatocellular carcinoma
    Carcinoma hepatocelular
    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 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine efficacy of Sorafenib in advanced hepatocellular carcinoma (stage C of BCLC classification) after radiological progression.
    Determinar eficacia de Sorafenib en pacientes con carcinoma hepatocelular (estadio C de la clasificación de BCLC) tras la progresión radiológica.
    E.2.2Secondary objectives of the trial
    -To determine safety of Sorafenib in advanced hepatocellular carcinoma (stage C of BCLC classification) after radiological progression.
    -To assess quality of life.
    -To evaluate adherence to Sorafenib treatment.

    To determine if growth factors related to neoangiogenesis, as EGF,FGF-2,VEGF and PDGF, could be biomarkers of respond to Sorafenib treatment in advanced hepatocellular carcinoma.
    - Determinar seguridad de Sorafenib en el carcinoma hepatocelular avanzado (estadio C de la BCLC) tras la progresión radiológica.
    - Valorar la calidad de vida.
    - Evaluar la adherencia al tratamiento con Sorafenib.

    Determinar si factores de crecimiento relacionados con la neoangiogénesis, como EGF, FGF-2, VEGF y PDGF, pueden ser biomarcadores de respuesta del carcinoma hepatocelular avanzado al tratamiento con Sorafenib.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patient older than 18 years old.
    2. Diagnosis of advanced HCC according to the AASLD Guidelines.
    3. HCC stage B with contraindication to transarterial chemoembolization (TACE) or stage C according to Barcelona Clinic Liver Cancer (BCLC) staging classification.
    4. Sorafenib treatment-naive patient.
    5. Child-Pugh class A (5-6 points) or class B (7 points), without ascites (mild ascites controlled with diuretics is allowed) and encephalopathy. Child-Pugh status must be calculated based on clinical findings and laboratory results during 30 days before inclusion in the study.
    6. ECOG Performance Status lower than 2.
    7. Adequate liver, renal and bone marrow function as shown by:
    AST y ALT lower than 5 x ULN (upper limit of normal); bilirubin lower than 2 mg/dL; INR lower than 2; absolute neutrophil count (ANC) higher than 1.2 x 103 per ml ; platelets higher than 70 x 103 per ml ; serum creatinine lower than 1.5 mg/dL.
    8. Written informed consent.
    9. Women of chilbearing potential (WOCBP) must have a negative serum pregnancy test performed in the screening visit.
    WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilizatiion (hysterectomy, bilateral tubal ligation or bolateral oophorectomy) or is not postmenopausal. Post menopause is defined as an amenorrhea state longer than 12 consecutive months.
    10. Men and women enrolled in this trial must used adequate barrier bith control measure since two weeks prior to the start of investigational product, during the course of the trial and two weeks after the last dose of investigational product.
    1. Pacientes hombres o mujeres mayores de edad.
    2. Diagnóstico de hepatocarcinoma celular avanzado según los criterios de la AASLD.
    3. CHC en estadio B de la BCLC con contraindicación a quimioembolización transarterial o estadio C de la BCLC sin contraindicación alguna a Sorafenib.
    4. Paciente que vaya a iniciar tratamiento con Sorafenib por primera vez.
    5. Child-Pugh de clase A (5-6) y B-7 como máximo, sin encefalopatía. Se permitirá ascitis controlada con dieta y/o diuréticos.
    6. ECOG menor de 2.
    7. Función hepática, renal y de médula ósea adecuada confirmada con una analítica local realizada no más de 21 días previos a la inclusión del paciente en el estudio:
    AST y ALT < 5 x LSN (límite superior de normalidad)
    Bilirrubina < 2 mg/dL
    INR < 2
    Hemoglobina > 9.0 g/dL
    Neutrófilos absoluto > 1.2 x 103 /mL
    Plaquetas > 70 x 103 /mL
    Creatinina sérica < 1.5 mg/dL x LSN
    8. Consentimiento informado otorgado por escrito.
    9. Mujeres en edad fértil deberán obtener un reusltado negativo en la prueba de embarazo en suero, en la visita de selección.
    Como mujer en edad fértil se define cualquier mujer que haya experimentado la menarquía, no se haya sometido a una intervención quirúrgica de esterilización (histerectomía, ligadura bilateral de trompas u ovariohisterectomia) y no es post- menopausica. La post-menopausia se define como amenorrea durante más de 12 meses consecutivos.
    10. Los hombres y mujeres participantes en este estudio deben usar medidas anticoceptivas desde dos semanas antes de iniciar la toma del fármaco en estudio, durante la duración del estudio y dos semanas después de la última dosis del medicamento de investigación.
    E.4Principal exclusion criteria
    1. Prior liver transplantation.
    2. Known history of HIV infection.
    3. Previous/concurrent cancer (distinct from HCC) known during the last 3 years, except for cervical carcinoma in situ, basal cells carcinoma and superficial bladder tumors.
    4. History of cardiovascular disease:
    - uncontrolled hypertension, defined as systolic blood pressure higher than 150 mmHg or diastolic pressure higher than 90 mmHg despite optimal medical management.
    - active coronary disease, unstable or newly diagnosed angina or myocardial infarction less than 12 months prior to study entry.
    - cardiac arrhythmias requiring anti-arrhytmic therapy other than beta blockers or digoxin.
    - congestive heart failure higher than NYHA class 2.
    5. Subjects with history of bleeding diathesis.
    6. History of gastrointestinal bleeding within 30 days of randomizaion.
    7. Subjects with a history of esophageal varices bleeding without efffective therapy and/or treatment to prevent bleeding recurrence.
    8. Abuse to drugs, clinical or psychological states that might interfere in the participation or evaluation of study results.
    9. Subjects on warfarin, acenocumarol, fenprocumone.
    10.Female patients who are pregnant or breast feeding.
    11.Unable or unwilling subjects to give informed consent.
    1. Trasplante hepático previo.
    2. Antecedentes conocidos de infección por VIH.
    3. Tumores previos/actuales (diferentes del HCC) conocidos durante los 3 últimos años, excepto carcinoma cervical in situ, carcinoma de células basales y tumores superfciales de vejiga.
    4. Historial de enfermedad cardiovascular:
    - hipertensión descontrolada, definida como una presión sistólica mayor de 150 mmHg o una presión diastólica mayor de 90 mmHg pese a un manejo médico óptimo.
    - enfermedad coronaria activa, angina de reciente diagnóstico o inestable, o infarto de miocardio durante los últimos 12 meses antes de la inclusión en el estudio.
    - Arritmias cardiacas que requieren terapia anti- arritmia diferente de beta-boqueantes o digoxina.
    - Fallo cardiaco congestivo mayor de la clase 2 de la NYHA.
    5. Sujetos con historial de diatesis hemorrágicas.
    6. Historial de hemorragias gastrointestinales en los 30 días anteriores a la randomización.
    7. Sujetos con historial de varices esofágicas sin terapia eficaz para prevenir la recurrencia del sangrado.
    8. Drogas de abuso, estados psicológicos o clínicos que pudieran interferiren la participación o evaluación de los resultados del estudio.
    9. Sujetos en tratamiento con warfarina, acenocumarol o fenprocumona.
    10. Mujeres embarazadas o en periodo de lactancia.
    11. Incapacidad o reticencia para dar consentimiento informado.
    E.5 End points
    E.5.1Primary end point(s)
    Overall Survival (OS)
    Supervivencia global (SG)
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of the clinical trial
    Al finalizar el ensayo clínico
    E.5.2Secondary end point(s)
    1. Safety Variables.
    All subjects who receive at least one dose of Sorafenib will be valid for safety analysis.
    - Adverse Events (AEs): according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 of National Cancer Institute (NCI).
    All adverse events occurring after the subject included in the study until 30 days last treatment just as adverse event causality relationship with study drug, must be recorded in the subject?s clinical informs and subject?s case record form.
    The intensity or severity of adverse event should be documented using the NCI-CTCAE; version 3.0.If CTCAE grading does not exist for an AE, the severity of mild, moderate, severe and life-threatening, or grades 1-4, will be used.
    - Safety assessments: Results of blood test (hematology, serum chemistry, coagulation tests), vital signs data (heart rate, blood pressure, respiration rate and body temperature), weight, 12-lead electrocardiogram (ECG) and physical examinations.
    2. - Adherence to treatment.
    Drug Accountability: Sorafenib tablets accountability and the patient?s information in terms of lost of forgotten doses will be recorded in the subject?s clinical informs at each study visit.
    3. - Quality of life.
    Patient Questionnaires: the patient reports outcomes through EQ-5D questionnaire (or EuroQol Questionnaire: a generic utility measure used to characterize current health states) and FACT-Hep questionnaire (The Functional Assessment of Cancer Therapy- Hepatobiliary Questionnaire: measuring health-related quality of life in patients with hepatobiliary cancers).

    Exploratory Variable:
    Determine serological levels of growth factor related to neoangiogenesis, as EGF, FGF-2,VEGF and PDGF, by Bioplex technology.
    1.- Variables de seguridad.
    Todos los pacientes que reciban al menos una dosis de Sorafenib serán válidos para el análisis de seguridad.
    - Acontecimientos adversos (AAs) según los Criterios de Terminología Común de Eventos Adversos (NCI-CTCAE) versión 3.0 del Instituto Nacional de Cáncer (NCI).
    Todos los acontecimientos adversos que ocurran después de la inclusión de un paciente en el estudio hasta 30 días después del fin del tratamiento con Sorafenib así como la relación causal con el fármaco de estudio de cada uno de ellos, serán recogidos en el informe clínico del paciente en cada visita y en el cuaderno de recogida de datos (CRD).
    La intensidad o severidad del acontecimiento adverso se documentará usando el NCI-CTCAE versión 3.0. Si no existe el grado para un AA se utilizará leve, moderado, grave y amenaza a la vida, o los grados de 1 a 4.
    - Medidas de seguridad: resultados de análisis de sangre (hematología, bioquímica, coagulación), datos de constantes vitales (frecuencia cardiaca, presión arterial, frecuencia respiratoria y temperatura corporal), peso, electrocardiograma de 12 derivaciones y examen físico.
    2.- Adherencia al tratamiento.
    - Contabilidad de medicación: se hará un recuento de comprimidos de Sorafenib en cada visita del estudio y se anotará la información proporcionada por el paciente en cuanto a olvido o pérdida de dosis en el informe clínico del paciente en cada visita del estudio.
    3.- Calidad de vida.
    Cuestionarios al paciente: la calidad de vida en nuestro estudio nos vendrá determinada por los resultados notificados por los pacientes mediante el cuestionario de salud general (EQ-5D) y el cuestionario de ?Evaluación funcional de la terapia contra el cáncer- subescala hepatobiliar? (FACT- Hep) [11].

    Variable exploratoria:
    Determinar, mediante tecnología Bioplex, los niveles serológicos de factores de crecimiento relacionados con la neoangiogénesis, como EGF, FGF-2, VEGF y PDGF.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of study
    Al finalizar el estudio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Serological biomarkers
    Biomarcadores serológicos
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 concerned15
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    At the end of the follow-up of the last included patient in the study because the main endpoint is overall survival.
    Al final del seguimiento del último paciente incluido en el estudio porque la variable principal es supervivencia global.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 66
    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 state126
    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)
    the expected normal treatment
    El tratamiento habitual en la practica clínica
    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 Decision2012-06-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-05-22
    P. End of Trial
    P.End of Trial StatusOngoing
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