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    Summary
    EudraCT Number:2010-019522-13
    Sponsor's Protocol Code Number:GP13-301
    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:2011-11-11
    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 number2010-019522-13
    A.3Full title of the trial
    A randomized, controlled, double-blind Phase III trial to compare the efficacy, safety and pharmacokinetics of GP2013 plus CVP vs. MabThera® plus CVP, followed by GP2013 or MabThera® maintenance therapy in patients with previously untreated, advanced stage follicular lymphoma.
    Ensayo de fase III aleatorizado, controlado, doble ciego para comparar la eficacia, la seguridad y la farmacocinética de GP2013 más CVP frente a. MabThera® más CVP, seguido de tratamiento de mantenimiento con GP2013 o MabThera®, en pacientes con linfoma folicular en estadio avanzado no tratado previamente
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A randomized Phase III clinical trial to compare the efficacy and safety of the biosimilar rituximab GP2013 in combination with a standard chemotherapy (CVP) or rituximab MabThera in combination with a standard chemotherapy (CVP), including GP2013/MabThera maintenance therapy in patient with previously untreated advanced stage follicular lymphoma.
    Un ensayo de fase III aleatorizado para comparar la eficacia y la seguridad de GP2013 biosimilar de rituximab en combinación con una quimioterapia habitual (CVP) o MabThera rituximab en combinación con una quimioterapia habitual (CVP), que incluye el tratamiento de mantenimiento con GP2013/MabThera en pacientes con linfoma folicular en estadio avanzado no tratado previamente
    A.4.1Sponsor's protocol code numberGP13-301
    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 SponsorHEXAL AG (a Sandoz company)
    B.1.3.4CountryGermany
    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 supportHEXAL AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHEXAL AG (a Sandoz company)
    B.5.2Functional name of contact pointChristian Hosius
    B.5.3 Address:
    B.5.3.1Street AddressIndustriestrasse 25
    B.5.3.2Town/ cityHolzkirchen
    B.5.3.3Post codeD-83607
    B.5.3.4CountryGermany
    B.5.4Telephone number00498024 476 2982
    B.5.5Fax number00498024 476 5633
    B.5.6E-mailchristian.hosius@sandoz.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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGP2013 Solución para perfusión IV
    D.3.2Product code GP2013
    D.3.4Pharmaceutical form Concentrate 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 INNRituximab
    D.3.9.2Current sponsor codeGP2013
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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) 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.3.11.13.1Other medicinal product typeAnticuerpo monoclonal
    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 MabThera®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationPoland
    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 nameMabThera®
    D.3.4Pharmaceutical form Concentrate 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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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) 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.3.11.13.1Other medicinal product typeAnticuerpo monoclonal
    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
    Advanced stage follicular lymphoma.
    Linfoma folicular en estadio avanzado.
    E.1.1.1Medical condition in easily understood language
    cancer
    Cáncer.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10016910
    E.1.2Term Follicle centre lymphoma, follicular grade I, II, III stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10016909
    E.1.2Term Follicle centre lymphoma, follicular grade I, II, III stage III
    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 demonstrate comparability of the overall response rate in patients with previously untreated, advanced stage follicular lymphoma who receive GP2013-CVP combination treatment to patients who receive MabThera®-CVP treatment.
    Demostrar la comparabilidad de la tasa de respuesta global en pacientes con linfoma folicular en estadio avanzado no tratado previamente que reciben tratamiento de combinación con GP2013-CVP y en pacientes que reciben tratamiento con MabThera®-CVP.
    E.2.2Secondary objectives of the trial
    Other efficacy
    - To evaluate CR rate at the end of combination treatment period;
    - To evaluate PR rate at the end of combination treatment period;
    - To evaluate PFS, which is defined as time from date of randomization to date of first documented progression of disease, or death due to any cause;
    - To evaluate OS, which is defined as: time from date of randomization to date of death due to any cause.
    Safety
    - To describe safety of GP2013-CVP in comparison to MabThera®-CVP;
    - To evaluate the incidence of ADA formation against GP2013 and MabThera®.
    Pharmacokinetics/Pharmacodynamics
    - To evaluate the pharmacokinetics of GP2013 and MabThera®. To evaluate peripheral CD19+ Bcell count as a pharmacodynamic marker following treatment with GP2013-CVP and MabThera®- CVP.
    Exploratory
    - To explore the population pharmacokinetics of GP2013 and MabThera®.
    Otros criterios de eficacia
    - Evaluar la tasa de RC al final del período de tratamiento de combinación;
    - Evaluar la tasa de RP al final del período de tratamiento de combinación;
    - Evaluar la SLP, que se define como el tiempo transcurrido desde la aleatorización hasta la fecha de la primera progresión documentada de la enfermedad o la muerte por cualquier causa;
    - Evaluar la SG, que se define como el tiempo transcurrido desde la aleatorización hasta la fecha de muerte por cualquier causa.

    De seguridad
    - Describir la seguridad de GP2013-CVP en comparación con MabThera®-CVP;
    - Evaluar la incidencia de formación de ACF frente a GP2013 y MabThera®.

    Farmacocinéticos/farmacodinámicos
    - Evaluar la farmacocinética de GP2013 y MabThera®. Evaluar el recuento de linfocitos B CD19+ periféricos como marcador farmacodinámico tras el tratamiento con GP2013-CVP y MabThera®-CVP.

    Exploratorio
    - Explorar la farmacocinética poblacional de GP2013 y MabThera®.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this study have to meet all of the following criteria:
    1. Patient with previously untreated advanced stage, CD20-positive FL:
    a. Ann Arbor classification stage III/IV; and
    b. WHO histologic grade 1, 2 or 3a, as confirmed by central pathological testing.
    2. Patient age > or = 18 years.
    3. Patient with at least one measurable lesion (accurately measurable in at least 2 perpendicular dimensions);
    a. at least 1 measurable nodal lesion > 20 mm in the long axis; OR
    b. at least 1 measurable extranodal lesion with both long and short axes > or = 10 mm.
    4. Patient with ECOG performance status 0, 1 or 2.
    5. Patient with adequate cardiac function defined as cardiac ejection fraction > or = 45% as measured by 2D-ECHO or MUGA, without clinically significant abnormalities.
    6. Patient with the following laboratory values obtained during Screening (up to 21 days before randomization):
    a. hemoglobin > or = 10g/dL (unless abnormalities are due to histologically proven bone marrow involvement by lymphoma);
    b. absolute neutrophil count (ANC) > or = 1.5 x 10^9/L (unless abnormalities are due to histologically proven bone marrow involvement by lymphoma);
    c. platelet count > or = 100 x 10^9/L (unless abnormalities are due to histologically proven bone marrow involvement by lymphoma);
    d. total bilirubin < 2.0 x ULN (upper limit of normal) (unless Gilbert-Meulengracht syndrome is present);
    e. transaminases < 2.5 x ULN;
    f. serum creatinine level < 2 x ULN;
    g. negative serology for hepatitis B and C.
    7. Sexually active males who accept to use a condom during intercourse while taking the drug and for 12 months after stopping treatment as they should not father a child in this period. A condom is required to be used also by vasectomised men (as well as during intercourse with a male partner) in order to prevent delivery of the drug via seminal fluid.
    8. a) Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partner have been sterilized by vasectomy or other means, who accept to use a highly effective method of birth control while taking study drug and for 12 months after stopping treatment.
    OR
    b) Women who are considered post-menopausal and not of child bearing potential i.e. if they have had 6 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago (in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment).
    9. Patient has signed and dated informed consent documents according to local guidelines.
    Los pacientes elegibles para inclusión en este estudio tienen que cumplir todos los criterios siguientes:
    1. Paciente con LF CD20-positivo en estadio avanzado no tratado previamente:
    a. en estadio III/IV de Ann Arbor; y
    b. grado histológico 1, 2 ó 3a de la OMS, confirmado por una prueba anatomopatológica realizada centralmente.
    2. Edad > ó = 18 años.
    3. Paciente con al menos una lesión mensurable (exactamente mensurable en al menos 2 dimensiones perpendiculares);
    a. al menos una lesión ganglionar mensurable > 20 mm en el eje largo; O
    b. al menos 1 lesión extraganglionar mensurable con ejes largo y corto > ó = 10 mm.
    4. Estado funcional ECOG 0, 1 ó 2
    5. Paciente con una función cardíaca adecuada, definida como una fracción de eyección cardíaca > ó = 45% medida con ECO bidimensional o MUGA, sin anomalías clínicamente significativas.
    6. Paciente con los siguientes valores de laboratorio obtenidos durante la visita de selección (hasta 21 días antes de la aleatorización):
    a. hemoglobina > ó = 10g/dL (salvo que las anomalías se deban a afectación de la médula ósea por el linfoma demostrada histológicamente);
    b. recuento absoluto de neutrófilos (RAN) > ó = 1,5 x 109/l (salvo que las anomalías se deben a afectación de la médula ósea por el linfoma demostrada histológicamente);
    c. recuento de plaquetas > ó = 100 x 109/l (salvo que las anomalías se deben a afectación de la médula ósea por el linfoma demostrada histológicamente);
    d. bilirrubina total < 2,0 veces el límite superior de la normalidad (a menos que haya síndrome de Gilbert-Meulengracht).
    e. transaminasas < 2,5 x LSN;
    f. nivel de creatinina sérica < 2 x LSN;
    g. serología negativa para la hepatitis B y C.
    7. Varón sexualmente activo que acceda a utilizar preservativo en las relaciones sexuales durante la administración del medicamento y en los 12 meses siguientes a la terminación del tratamiento, ya que no debe engendrar un hijo durante este período. También deberán usar preservativo los varones vasectomizados (incluso en sus relaciones con una pareja masculina) para evitar el paso del fármaco a través del líquido seminal.
    8. a) Mujer en edad fértil, definida como la que tiene capacidad fisiológica de quedarse embarazada, incluidas aquellas cuyo trabajo, hábitos de vida u orientación sexual impidan la relación con una pareja masculina y las mujeres cuya pareja haya sido esterilizada con vasectomía u otros medios, que acepte utilizar un método anticonceptivo muy eficaz (se define en la sección 7.2.2.5.7) mientras esté tomando el fármaco del estudio y hasta 12 meses después del tratamiento.
    O BIEN
    b) Mujer posmenopáusica y que no esté en edad fértil, es decir, que haya tenido 6 meses de amenorrea natural (espontánea) con un perfil clínico apropiado (por ejemplo, edad adecuada, antecedentes de síntomas vasomotores) o se haya sometido a ovariectomía bilateral (con o sin histerectomía) o a ligadura de trompas al menos 6 semanas antes (en caso de ooforectomía sola, únicamente si su estado reproductivo ha sido confirmado en una evaluación de seguimiento de los niveles hormonales).
    9. El paciente ha firmado y fechado los documentos de consentimiento informado de acuerdo con las normas locales.
    E.4Principal exclusion criteria
    Patients eligible for this study must not meet any of the following criteria:
    1. Patient with Grade 3b (aggressive) FL or any histology other than FL grade 1, 2 or 3a.
    2. Patient with histological evidence of transformation to high grade or diffuse large B-cell lymphoma.
    3. Patient who has previously received any prior therapy for lymphoma (e.g. cytostatic or cytotoxic agents, radiotherapy, antibodies, anti-lymphoma vaccination, experimental treatments).
    4. Evidence of significant leukemic disease.
    5. Patient with evidence of central nervous system (CNS) involvement by lymphoma or any evidence of spinal cord compression by lymphoma.
    6. Patient with evidence of any uncontrolled, active infection (viral, bacterial or fungal).
    7. Patient receiving chronic doses of corticosteroids (> 20 mg of prednisone or > approximately 3 mg of dexamethasone per day; or equivalent doses of other steroid medications).
    8. Patient with any malignancy within 5 years prior to date of randomization, with the exception of adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma or nonmelanomatous skin cancer.
    9. Patient with a known hypersensitivity to any of the study treatment ingredients e.g. to recombinant human antibodies.
    10. Patient with concurrent serious illnesses, uncontrolled medical conditions, or other medical history including abnormal laboratory results, which in the investigator's opinion would be likely to interfere with a patient's participation in the study, or with the interpretation of study results:
    a. uncontrolled neurological disease (e.g. recurrent seizures despite existing anticonvulsant therapy);
    b. neuropathy > grade 1, neuromuscular disease;
    c. severe disturbance of liver function;
    d. severe constipation;
    e. cystitis or other ongoing infections;
    f. disturbance of micturition;
    g. severe chronic obstructive pulmonary disease with clinically manifest hypoxemia (dyspnea > grade 1);
    h. uncontrolled hypertension;
    i. history of stroke or cerebral ischemia (within 6 months prior to randomization);
    j. history of myocardial infarction or other clinically significant myocardial disease (within 6 months prior to randomization) or unstable angina (> or = NYHA Grade II);
    k. inadequate cardiac function defined as cardiac ejection fraction < 45% as measured by 2DECHO or MUGA;
    l. known infection with HIV according to patient history;
    m. evidence of ongoing drug or alcohol abuse within the last 6 months before randomization;
    n. evidence of tuberculosis infection as defined by either a positive PPD skin test (the size of induration will be measured after 48-72 hours, and a positive result is defined as an induration of (> or = 5 mm or according to local guidelines) or a positive QuantiFERON TB-Gold test. Patients with evidence of latent tuberculosis may enter the study after evaluation by an appropriate specialist and after sufficient treatment has been initiated according to local medical practice.
    11. Patient has had major surgery, open biopsy or trauma within 4 weeks prior to date of randomization (lymph node biopsy is not regarded as major surgery), or expects the need for major surgery during the course of study treatment.
    12. Female patient who is nursing (lactating/breast-feeding), pregnant or planning a pregnancy within 12 months after the last infusion of study drug; where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
    13. Patient is receiving concurrent therapy with any other investigational medicinal product within the last 30 days or 5 times the half-life, whichever is longer, prior to randomization.
    14. Patient plans to receive live vaccines during the study or has received live vaccines 4 weeks prior to date of randomization.
    15. Patient is using growth factors to meet study eligibility requirements during Screening period.
    Los pacientes elegibles para este estudio no deberán cumplir ninguno de los criterios siguientes:
    1. Paciente con LF grado 3b (agresivo) o con histología distinta de un LF grado 1, 2 ó 3a.
    2. Paciente con evidencia histológica de transformación en linfoma de alto grado de malignidad o en linfoma difuso de linfocitos B grandes.
    3. Paciente que ha recibido previamente cualquier tratamiento para el linfoma (por ejemplo, agentes citostáticos o citotóxicos, radioterapia, anticuerpos, vacunación contra el linfoma, tratamientos experimentales).
    4. Evidencia de enfermedad leucémica significativa.
    5. Paciente con evidencia de afectación del sistema nervioso central (SNC) por el linfoma o de comprensión de la médula espinal por el linfoma.
    6. Paciente con evidencia de infección activa (viral, bacteriana o micótica) no controlada.
    7. Paciente que reciba dosis crónicas de corticosteroides (> 20 mg de prednisona o aproximadamente > 3 mg de dexametasona al día; o dosis equivalente de otros corticoesteroides).
    8. Paciente con enfermedad maligna en los 5 años anteriores a la aleatorización, con excepción del carcinoma in situ del cuello del útero adecuadamente tratado, carcinoma basocelular o epidermoide o cáncer de piel distinto del melanoma.
    9. Paciente con hipersensibilidad conocida a cualquiera de los componentes del tratamiento del estudio, como los anticuerpos humanos recombinantes.
    10. Paciente con enfermedad grave concomitante, enfermedades no controladas u otros antecedentes que incluyan resultados analíticos anormales que en opinión del investigador sea probable que interfieran en la participación del paciente en el estudio, o en la interpretación de los resultados de éste:
    a. enfermedad neurológica no controlada (por ejemplo, convulsiones recurrentes a pesar del tratamiento anticonvulsivo);
    b. neuropatía > grado 1, enfermedad neuromuscular;
    c. alteración graves de la función hepática.
    d. Estreñimiento severo;
    e. cistitis u otras infecciones en curso;
    f. trastorno de la micción;
    g. enfermedad pulmonar obstructiva crónica grave con hipoxemia clínicamente manifiesta (disnea > grado 1);
    h. hipertensión no controlada;
    i. antecedentes de ictus o de isquemia cerebral (en los 6 meses previos a la aleatorización);
    j. antecedentes de infarto de miocardio u otra enfermedad miocárdica clínicamente significativa (en los 6 meses anteriores a la aleatorización) o angina de pecho inestable (> or = grado II de la NYHA);
    k. función cardíaca inadecuada, definida como una fracción de eyección cardíaca < 45% medida por ECO bidimensional o MUGA;
    l. infección conocida por el VIH según los antecedentes del paciente;
    m. evidencia de consumo excesivo de drogas o alcohol en los 6 meses previos a la aleatorización;
    n. evidencia de infección tuberculosa, definida por una prueba cutánea de PPD positiva (el tamaño de la induración se medirá después de 48-72 horas y se define como resultado positivo una induración (> or = 5 mm o según la normativa local) o un resultado positivo en la prueba QuantiFERON TB-Gold. Los pacientes con evidencia de TB latente podrán entrar en el estudio previa evaluación por un especialista y después de la instauración de tratamiento suficiente de acuerdo con la práctica local.
    11. Paciente sometido a cirugía mayor o biopsia abierta o que haya sufrido traumatismo en las 4 semanas previas a la fecha de aleatorización (la biopsia de ganglios linfáticos no se considera cirugía mayor), o para el que se prevea la necesidad de una operación de cirugía mayor durante el tratamiento del estudio.
    12. Mujer que esté amamantando o embarazada o tenga previsto quedar embarazada durante los 12 meses siguientes a la última perfusión de fármaco del estudio, entendiéndose el embarazo como el estado de la mujer desde la concepción hasta el final de la gestación, confirmada por un análisis de hCG positivo (> 5 mUI/ml).
    13. Paciente que este recibiendo tratamiento concomitante con otro producto en investigación en los 30 días o el quíntuplo de la semivida, lo que sea más largo, antes de la aleatorización.
    14. Paciente que tenga previsto recibir vacunas de virus vivos durante el estudio o que las ha recibido dentro de las 4 semanas anteriores a la aleatorización.
    15. Paciente que utilice factores de crecimiento para cumplir los requisitos de elegibilidad del estudio durante el período de selección.
    E.5 End points
    E.5.1Primary end point(s)
    Overall response rate at the end of combination treatment period using modified response criteria for lymphoma. Overall response rate is defined as the proportion of patients whose best overall disease response is either complete response or partial response at the end of the combination treatment period.
    Tasa de respuesta global (TRG) al final del periodo de tratamiento de combinación, determinada usando criterios de respuesta modificados en el linfoma). La TRG se define como la proporción de pacientes cuya mejor respuesta global de la enfermedad sea respuesta completa o respuesta parcial al final del período de tratamiento de combinación.
    E.5.1.1Timepoint(s) of evaluation of this end point
    month 6
    mes 6
    E.5.2Secondary end point(s)
    Other efficacy
    * Complete response
    * Partial response
    * Progressive free survival (from date of randomization to date of first documented progression of disease, or death due to any cause.)
    * Overall survival (from date of randomization to date of death due to any cause)
    Safety:
    * Percentage of patients with adverse event and laboratory test abnormalities
    * Percentage of patients with anti-drug antibodies formation
    Pharmacokinetics/Pharmacodynamics:
    * Pharmacokinetic variables (Cmax, Cmin)
    * CD19+ B-cell count (AUEC0-21 days)
    Exploratory:
    * Pharmacokinetic variables (Cmax, Cmin)
    Otros objetivos de eficacia:
    - Respuesta completa
    - Respuesta parcial
    - Supervivencia libre de progresión (desde la fecha de la aleatorización hata la fecha de la primera progresión documentada de la enfermedad o la muerte por cualquier causa)
    - Supervivencia global (desde la fecha de la aleatorización hasta la fecha de la muerte por cualquier causa).

    Seguridad:
    - Porcentaje de pacientes con acontecimientos adversos y anomalías clínicas.
    - Porcentaje de pacientes con formación de anticuerpos antifármco.

    Farmacocinética/Farmacodinamia:
    - Variables farmacocinéticas (Cmax, Cmin)
    - Recuento de células B CD19+ (AUEC0-21 días)
    Exploratorio:
    - Variables farmacocinéticas (Cmax, Cmin)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Other efficacy
    * CR: after 6 months and at the end of maintenance
    * PR: after 6 months and at the end of maintenance
    * PFS: end of 3-year follow-up period
    * OS: at the end of maintenance
    Safety:after 6 months and at the end of maintenance
    Pharmacokinetics/Pharmacodynamics: after 6 months and at the end of maintenance
    Exploratory: after 6 months and at the end of maintenance
    Otros de eficacia
    * RC: después de 6 meses y al final del mantenimiento
    * RP: después de 6 meses y al final del mantenimiento
    * SLP: final del periodo de seguimiento de 3 años
    * SG: al final del mantenimiento
    Seguridad: después de 6 meses y al final del mantenimiento
    Farmacocinética/Farmacodinamia: después de 6 meses y al final del mantenimiento
    Exploratorio: después de 6 meses y al final del mantenimiento
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response 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
    Comparability
    Comparabilidad
    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 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 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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    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
    Argentina
    Australia
    Austria
    Brazil
    Bulgaria
    Colombia
    France
    Germany
    Hungary
    India
    Israel
    Malaysia
    Netherlands
    New Zealand
    Peru
    Poland
    Portugal
    Romania
    Russian Federation
    Spain
    Ukraine
    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
    Last visit, last subject
    Última visita, último sujeto.
    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 years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 309
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 309
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 183
    F.4.2.2In the whole clinical trial 618
    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)
    Patients will be treated as per standard of care after the end of the trial.
    Note: Patients will be treated as per SOC after the 6months combination treatment period. Maintenance monotherapy with MabThera/GP2013 will be provided.
    Los pacientes serán tratados según el cuidado habitual después del final del ensayo. Nota: Los pacientes serán tratados según el cuidado habitual después del periodo de tratamiento de combinación de 6 meses. Se proporcionará mantenimiento en monoterapia con MabThera/GP2013.
    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 Decision2011-10-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-09-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-01-22
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