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    Summary
    EudraCT Number:2011-005178-43
    Sponsor's Protocol Code Number:OMB115991
    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:2012-01-19
    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 number2011-005178-43
    A.3Full title of the trial
    A Phase II, Multi-centre Study Investigating the Safety and Efficacy of Ofatumumab and Bendamustine Combination in Patients with Untreated or Relapsed Chronic Lymphocytic Leukaemia (CLL).
    Estudio fase II, multicéntrico para investigar la seguridad y eficacia de la combinación de ofatumumab y bendamustina en pacientes con leucemia linfocítica crónica (LLC) no tratada o en recaída.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of a new drug combination to treat Chronic Lymphocytic Leukemia.
    Estudio de una nueva combinación de fármacos para el tratamiento de la leucemia linfocítica crónica.
    A.4.1Sponsor's protocol code numberOMB115991
    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 SponsorGlaxoSmithKline, 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 supportGlaxoSmithKline
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Ltd
    B.5.2Functional name of contact pointClinical Trials Helpdesk
    B.5.3 Address:
    B.5.3.1Street AddressIron Bridge Road, Stockley Park West
    B.5.3.2Town/ cityUxbridge, Middlesex
    B.5.3.3Post codeUB11 1BU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number44208990 4466
    B.5.5Fax number44208990 1234
    B.5.6E-mailGSKClinicalSupportHD@gsk.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 Yes
    D.2.1.1.1Trade name ARZERRA
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxo Group Limited
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/08/581
    D.3 Description of the IMP
    D.3.1Product nameOfatumumab
    D.3.2Product code GSK1841157
    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 INNofatumumab
    D.3.9.1CAS number 679818-59-8
    D.3.9.2Current sponsor codeGSK1841157
    D.3.9.4EV Substance CodeSUB25221
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 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.2.1.1.1Trade name LEVACT
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma GmbH, Postfach 50 01 66, 80971 München, Germany
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameBendamustine
    D.3.4Pharmaceutical form Powder for 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 INNbendamustine hydrochloride
    D.3.9.1CAS number 3543-75-7
    D.3.9.3Other descriptive namebendamustine
    D.3.9.4EV Substance CodeSUB00696MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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.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 No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Untreated or Relapsed Chronic Lymphocytic Leukaemia
    Leucemia linfocítica crónica (LLC) no tratada anteriormente o en recaída.
    E.1.1.1Medical condition in easily understood language
    Chronic lymphocytic leukemia is a condition where too many abnormal white blood cells are produced which build up and reduce the number of normal blood cells that can be made.
    La leucemia linfocítica cróncia es una patología en la que se produce un aumento excesivo en los linfocitos y se reduce el número normal de células sanguíneas que pueden producirse.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10008968
    E.1.2Term Chronic lymphocytic leukaemia stage A(0)
    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
    The primary objective of this study is to evaluate the investigator assessed overall response rate (ORR), using the IWCLL updated NCI-WG guidelines [Hallek 2008], in two populations i.e., subjects with previously untreated CLL and subjects with relapsed CLL administered ofatumumab plus bendamustine.
    El objetivo primario de este estudio es evaluar la tasa de respuesta global (TRG) valorada por el investigador, utilizando las directrices del International Workshop for Chronic Lymphocytic Leukaemia (IWCLL) actualizadas por el Grupo de Trabajo patrocinado por el Instituto Nacional del Cáncer (NCI-WG) [Hallek 2008] en dos poblaciones, sujetos con LLC no tratada anteriormente y sujetos con LLC en recaída, tratados con ofatumumab más bendamustina.
    E.2.2Secondary objectives of the trial
    - To evaluate overall response rate with CT scan assessment, complete response rate with and without CT scan assessment, progression-free-survival, overall survival, time to response, duration of response, time to progression and time to next therapy in the two separate subject populations i.e., subjects with untreated CLL and subjects with relapsed CLL.
    - To evaluate the safety and tolerability in the two separate subject populations i.e., subjects with untreated and subjects with relapsed CLL.
    - To evaluate disease, prognostic and biological marker correlation with clinical response in the two separate subject populations i.e. subjects with untreated CLL and subjects with relapsed CLL.
    - Evaluar la tasa de respuesta global con evaluación por TC, tasa de respuesta completa con y sin evaluación por TC, supervivencia libre de progresión, supervivencia global, tiempo hasta la respuesta, duración de la respuesta, tiempo hasta la progresión y tiempo hasta el siguiente tratamiento es las dos poblaciones de sujetos: sujetos con LLC no tratada y sujetos con LLC en recaída.
    - Evaluar la seguridad y tolerabilidad en las dos poblaciones de sujetos: sujetos con LLC no tratada y sujetos con LLC en recaída.
    - Evaluar la correlación de marcadores pronósticos, biológicos y de enfermedad con la respuesta clínica en las dos poblaciones, es decir, sujetos con LLC no tratada y sujetos con LLC en recaída.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects eligible for enrolment in the study must meet all of the following criteria:
    1. A diagnosis of CLL defined by:
    a. A circulating B-lymphocyte count of >=5,000/?L at study entry or at any time in the past.
    b. Flow cytometry confirmation of immunophenotype with CD5, CD19, CD20, CD23, CD79b, and surface Ig prior to first dose of study treatment.

    2. Active disease and indication for treatment based on the IWCLL updated NCI-WG guidelines [Hallek 2008], defined by presence of at least any one of the following conditions:

    ? Evidence of progressive marrow failure as manifested by development or worsening of anaemia and/or thrombocytopenia.
    ? Massive (i.e. at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
    ? Massive nodes (i.e. at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
    ? Progressive lymphocytosis with an increase of more than 50% over a two-month period or a lymphocyte doubling time of less than 6 months.
    In subjects with initial blood lymphocyte counts of less than 30x109/L, lymphocyte doubling time should not be used as a single parameter to define a treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
    ? A minimum of any one of the following disease-related symptoms must be present:
    a. Unintentional weight loss >= 10% within the previous six months;
    b. Fevers > 100.5°F (38.0°C) for >= 2 Weeks without evidence of infection;
    Or
    c. Night sweats for more than 1 month without evidence of infection.

    3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.









    4. Age >= 18 years.

    5. Signed written informed consent from either the subject, or their legally acceptable representative if the subject is incapable of giving their own consent, prior to performing any study-specific tests or procedures.

    Subjects enrolled into the previously untreated subject cohort must also meet all of the following criteria:
    6. No prior treatment for CLL (prior corticosteroid immunosuppression treatment for autoimmune hemolytic anaemia and idiopathic thrombocytopenic purpura (ITP) is permitted).

    7. Considered inappropriate for fludarabine-based therapy for reasons that include, but are not limited to, advanced age or presence of co-morbidities.

    Subjects enrolled into the relapsed subject cohort must also meet the following criteria:
    8. Relapsed CLL: defined as a subject who has received at least one prior CLL therapy and previously achieved a complete or partial remission/response lasting at least 6 months [Hallek, 2008].
    Sólo serán elegibles para participar en el estudio los sujetos que cumplan todos los criterios siguientes:

    1. Diagnóstico de LLC definida por:
    a. Número de linfocitos B circulantes >=5.000/µL en la inclusión en el estudio o en cualquier momento del pasado.
    b. Confirmación por citometría de flujo de inmunofenotipo con CD5, CD19, CD20, CD23, CD79b e Ig de superficie antes de la primera dosis de tratamiento del estudio.
    2. Enfermedad activa e indicación de tratamiento basada en las directrices del IWCLL actualizadas por el NCI-WG [Hallek], definida por la presencia de al menos una de las siguientes condiciones:
    - Evidencia de insuficiencia progresiva de la médula ósea maifestada por el desarrollo o empeoramiento de anemia y/o trombocitopenia.
    - Esplenomegalia masiva (al menos 6 cm por debajo del reborde costal izquierdo) o progresiva o sintomática.
    - Linfadenopatía masiva (al menos 10 cm de diámetro más largo) o progresiva o sintomática.
    - Linfocitosis progresiva con un incremento de más del 50% durante un periodo de 2 meses o tiempo hasta la duplicación del número de linfocitos inferior a 6 meses.
    En los sujetos con un recuento inicial de linfocitos en sangre inferior a 30x109/L, el tiempo hasta la duplicación del número de linfocitos no debe utilizarse como único parámetro para definir la indicación de tratamiento. Se deben excluir otros factores que contribuyan a la linfocitos o linfadenopatía distintos de la LLC (por ejemplo, infecciones).
    - Como mínimo uno de los siguientes síntomas relacionados con la enfermedad:
    a. Pérdida de peso no intencionada >=10% en los 6 meses anteriores
    b. Fiebre >38ºC durante >=2 semanas sin evidencia de infección
    O
    c. Sudoración nocturna durante más de 1 mes sin evidencia de infección.
    3. Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0-2.
    4. Edad >=18 años.
    5. Se debe obtener el consentimiento informado del sujeto, o de su representante legal si el sujeto no es capaz de dar su propio consentimiento, antes de realizar cualquiera de los procedimientos o pruebas específicas del estudio.
    Los sujetos reclutados en la cohorte de sujetos no tratados anteriormente también deben cumplir los siguientes criterios:
    6. Los sujetos no deben haber recibido ningún tratamiento anterior para la LLC (el tratamiento inmunosupresor anterior con corticosteroides para el tratamiento de la anemia hemolítica autoinmune y la púrpura trombocitopénica idiopática (PTI) está permitido).
    7. Sujetos que se consideren inadecuados para tratamiento con fludarabina por razones que incluyan, pero no se limiten a, edad avanzada o presencia de otras enfermedades simultáneamente.
    Los sujetos reclutados en la cohorte de sujetos con LLC en recaída también deben cumplir el siguiente criterio:
    8. LLC en recaída: definida como un sujeto que ha recibido al menos una terapia anterior para la LLC y anteriormente ha alcanzado una remisión/respuesta completa o parcial de al menos 6 meses de duración [Hallek, 2008].
    E.4Principal exclusion criteria
    Subjects meeting any of the following criteria must not be enrolled in the study:

    1. Refractory CLL: defined as treatment failure (failure to achieve a CR or PR) or disease progression within 6 months of the last anti-CLL therapy [Hallek, 2008].

    2. Previous autologous or allogeneic stem cell transplantation.

    3. Active autoimmune hemolytic anaemia (AIHA) and idiopathic thrombocytopenic purpura (ITP) requiring corticosteroid therapy >25 mg prednisone (or equivalent) or chemotherapy.

    4. Known transformation of CLL (e.g. Richter?s).

    5. Known central nervous system involvement by CLL.

    6. Screening laboratory values:
    a. Platelets < 100 x 109/L (unless due to CLL involvement of the bone marrow).
    b. Neutrophils < 1.5 x 109/L (unless due to CLL involvement of the bone marrow).
    c. Serum creatinine > 1.5 times the upper limit of normal (ULN); subjects with a serum creatinine > 1.5 ULN will be eligible if the calculated creatinine clearance [Cockcroft, 1976] is ? 30 mL/min.
    d. Total bilirubin > 1.5 times ULN (unless due to liver involvement by CLL or Gilbert?s disease).
    e. Transaminases > 2.5 times ULN.

    7. Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, active Hepatitis C, and known Human Immunodeficiency Virus (HIV) disease. All HIV-positive subjects are excluded from this study, regardless of whether they have an Acquired Immunodeficiency Syndrome (AIDS) defining disease and/or are on antiviral therapy.

    8. Other past or current malignancy (with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix or breast) unless the tumour was successfully treated with curative intent at least 2 years prior to trial entry.*

    9. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to first study treatment, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities.*

    10. History of significant cerebrovascular disease or event with significant symptoms or sequelae.*

    11. Glucocorticoid use, unless given in doses ? 25mg/Day prednisone (or equivalent) for <7 Days for exacerbations other than CLL (e.g. asthma).*

    12. Positive serology for Hepatitis B (HB) defined as a positive test for Hepatitis B surface antigen (HBsAg). In addition, if negative for HBsAg but Hepatitis B core antibody (HBcAb) positive, a Hepatitis B Virus (HBV) DNA test will be performed and if positive the subject will be excluded.

    If HBV DNA is negative, subject may be included but must undergo HBV DNA monitoring at Cycles 2, 3, 4, 5 and 6 depending on the number of Cycles administered and during the follow-up phase at the 3 Month and 6 Month post drug visits. Prophylactic antiviral therapy may be initiated at the discretion of the investigator. Please see Table 5 for further details.

    13. Known or suspected hypersensitivity to ofatumumab or bendamustine that in the opinion of the investigator is a contraindication to their participation in the present study.

    14. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 Weeks prior to first study treatment dose, whichever is longer, or participation in any other interventional clinical study.

    15. Known or suspected inability to comply with the study protocol.

    16. Lactating women, women with a positive pregnancy test at Visit 1 or women (of childbearing potential) as well as men with partners of childbearing potential, who are not willing to use adequate contraception from study start through one year following last ofatumumab dose. Adequate contraception is defined as abstinence, oral hormonal birth control, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device, and male partner sterilisation if male partner is sole partner for that subject. For females in the USA, the use of a double barrier method is also considered adequate (condom or occlusive cap plus spermicidal agent).

    *Subjects can participate in the study if in the opinion of the investigator it is thought not to affect the subject?s safety, the conduct of the study or the interpretation of the data.
    Los sujetos que cumplan cualquiera de los siguientes criterios no deben ser incluidos en el estudio:

    1. LLC refractaria: definida como fracaso del tratamiento (fracaso para alcanzar una RC o RP) o progresión de la enfermedad en los 6 meses siguientes a la última terapia anti-LLC [Hallek, 2008].
    2. Trasplante autólogo o alogénico previo de células madre.
    3. Anemia hemolítica autoinmune activa (AHAI) y púrpura trombocitopénica idiopática (PTI) que requiera corticoterapia con >25 mg de prednisona (o equivalente) o qumioterapia.
    4. Transformación conocida de la LLC (por ejemplo de Richter).
    5. Afectación conocida del SNC por la LLC.
    6. Valores de laboratorio en la selección:
    a. Plaquetas >100 x 109/L (a menos que se deba a afectación de la médula ósea por la LLC).
    b. Neutrófilos <1,5 x 109/L (a menos que se deba a afectación de la médula ósea por la LLC).
    c. Creatinina en suero >1,5 veces por encima del límite superior normal (LSN); los sujetos con un valor de creatinina en suero >1,5 LSN serán elegibles si el aclaramiento de creatinina calculado [Cockcroft, 1976] es ?30 mL/min.
    d. Bilirrubina total >1,5 veces por encima del LSN (a menos que se deba a afectación hepática por la LLC o la enfermedad de Gilbert).
    e. Transaminasas >2,5 veces por encima del LSN.
    7. Enfermedad infecciosa activa actual o crónica que requiera tratamiento sistémico con antibióticos, antifúngicos o antivirales, incluidas, pero no limitadas a infección renal crónica, infección pulmonar crónica con bronquiectasias, tuberculosis, hepatitis C activa y enfermedad conocida por el virus de la inmunodeficiencia humana (VIH). Todos los sujetos VIH-positivos serán excluidos del estudio, a menos que tengan el síndrome de inmunodeficiencia adquirida (SIDA) y/o estén en tratamiento con antivirales.
    8. Otra neoplasia antigua o actual (excepto el carcinoma basocelular o el carcinoma in situ de cervix o mama) a menos que el tumor haya sido tratado con éxito como mínimo 2 años antes de la inclusión en el estudio.*
    9. Cardiopatía clínicamente significativa como angina inestable, infarto agudo de miocardio en los 6 meses anteriores al primer tratamiento del estudio, insuficiencia cardiaca congestiva y arritmias que requieran tratamiento, excepto las extrasístoles o trastornos menores de la conducción.*
    10. Historia de enfermedad o acontecimiento cerebrovascular significativo con síntomas o secuelas significativas.*
    11. Empleo de glucocorticoides, a menos que se utilicen dosis <=25 mg/día de prednisona (o equivalente) durante <7 días para exacerbaciones de otras enfermedades distintas de la LLC (por ejemplo, asma).*
    12. Serología de hepatitis B (HB) positiva definida como antígeno de superficie de hepatitis B (HBsAg) positivo. Si el HBsAg es negativo pero los anticuerpos nucleares (core) de hepatitis B (HBcAb) son positivos, se debe hacer una análisis de ADN del virus de la hepatitis B (VHB) y si el resultado es positivo el sujeto será excluido.
    Si el ADN del VHB es negativo, el sujeto podrá ser incluido pero deberá monitorizarse el ADN del VHB en los Ciclos 2, 3, 4, 5 y 6 dependiendo del número de ciclos de tratamiento y durante la fase de seguimiento a los 3 y 6 meses de la última administración del tratamiento del estudio. Se puede iniciar terapia antiviral profiláctica si el investigador lo considera apropiado. Para más detalles consultar la Tabla 5.
    13. Sospecha o confirmación de hipersensibilidad a ofatumumab o bendamustina que, a juicio del investigador, sea una contraindicación para la participación del sujeto en el estudio.
    14. Tratamiento con cualquier fármaco no comercializado cocnocido o terapia experimental en las 5 semividas terminales o 4 semanas anteriores a la primera dosis de tratamiento del estudio, lo que sea más largo, o participación en cualquier otro estudio de investigación.
    15. Sospecha o confirmación de incapacidad para cumplir con el protocolo del estudio.
    16. Mujeres en periodo de lactancia, mujeres con una prueba de embarazo positiva en la Visita 1 o mujeres (potencialmente fértiles) y hombres con una pareja potencialmente fértil, que no estén dispuestos a utilizar un método anticonceptivo adecuado desde el inicio del estudio y hasta un año después de la última dosis de ofatumumab. Un método anticonceptivo adecuado se define como abstinencia, anticonceptivo hormonal oral, implante de levonorgestrel, anillo vaginal estrogénico, parches anticonceptivos percutáneos, dispositivo intrauterino y esterilización del varón si es la única pareja sexual de la paciente. En las mujeres de EEUU, el empleo de un método de doble barrea también se considera adecuado (preservativo o capuchón oclusivo más espermicida).
    *Los sujetos podrán participar en el estudio si el investigador opina que no afectará a la seguridad del sujeto, la realización del estudio o la interpretación de los datos.
    E.5 End points
    E.5.1Primary end point(s)
    Overall response rate (ORR) as determined by Investigator evaluation, is the percentage of subjects achieving an objective response (i.e., partial response or better), using the IWCLL updated NCI-WG guidelines [Hallek 2008]. Response assessment is planned at the following time-points:
    - After 3 Cycles of ofatumumab plus bendamustine treatment.
    - After 6 Cycles of ofatumumab plus bendamustine treatment.
    - After the last dose, if not after 6 cycles, of ofatumumab plus bendamustine treatment.
    La tasa de respuesta global (TRG) evaluada por el investigador, es el porcentaje de sujetos que alcanzan una respuesta objetiva (es decir, respuesta parcial o mejor) utilizando las directrices del IWCLL actualizadas por el NCI-WG [Hallek, 2008]. La evaluación de la respuesta está prevista en los siguientes momentos :
    - Tras 3 ciclos de tratamiento con ofatumumab más bendamustina.
    - Tras 6 ciclos de tratamiento con ofatumumab más bendamustina.
    - Tras la última dosis, si no es después de 6 ciclos, de tratamiento con ofatumumab más bendamustina.
    E.5.1.1Timepoint(s) of evaluation of this end point
    - After 3 Cycles of ofatumumab plus bendamustine treatment. Last Subject = approx. Nov-2012
    - After 6 Cycles of ofatumumab plus bendamustine treatment. Last Subject = approx. Feb-2013
    - After the last dose, if not after 6 cycles, of ofatumumab plus bendamustine treatment. Last Subject = approx. Feb-2013
    - Tras 3 ciclos de tratamiento con ofatumumab más bendamustina. Último paciente= aprox. Nov. 2012
    - Tras 6 ciclos de tratamiento con ofatumumab más bendamustina. Último paciente= aprox. Feb. 2013
    - Tras la última dosis, si no es después de 6 ciclos, de tratamiento con ofatumumab más bendamustina. Último paciente = Feb.2013
    E.5.2Secondary end point(s)
    ? Overall Response Rate (ORR) with CT-scan assessment as determined by Investigator evaluation, is the percentage of subjects achieving an objective response (i.e., partial response or better), using the IWCLL updated NCI-WG guidelines [Hallek 2008]. Response assessment is planned at the following time-points:
    - After 3 Cycles of ofatumumab plus
    bendamustine treatment.
    - After 6 Cycles of ofatumumab plus
    bendamustine treatment.
    - After the last dose, if not after 6
    cycles, of ofatumumab plus bendamustine
    treatment.
    ? Complete responses rate (CRR) as determined by Investigator evaluation, using the IWCLL updated NCI-WG guidelines [Hallek 2008], with and without CT scan assessment.
    ? Progression free survival (PFS).
    ? Overall survival (OS).
    ? Time to response and duration of response.
    ? Time to progression and time to next therapy.
    ? Incidence and severity of adverse events.
    ? Incidence and severity of serious adverse events.
    ? Incidence and severity of infusion reactions.
    ? Frequency of transfusions.
    ? Incidence of autoimmune hemolytic anaemia (AIHA).
    ? Development of Human Anti Human Antibodies (HAHA).
    ? Incidences of Grade 3 and 4 infections and myelosuppression (anaemia, neutropenia, thrombocytopenia).
    ? Changes in B-cell levels.
    ? Change in IgG, IgA, IgM quantities.
    ? Improvement of ECOG (Eastern Cooperative Oncology Group) performance status.
    ? Improvement in constitutional symptoms.
    ? Improvement in fatigue.
    ? Minimal Residual Disease (MRD), for subjects achieving a CR, as determined by flow cytometry.
    ? Cytogenetics by fluorescent in situ hybridization (FISH).
    ? ?2 microglobulin.
    ? IgVH mutational status, VH3-21 usage.
    ? ZAP70.
    1. La tasa de respuesta global (TRG) evaluada con TC, determinada por el investigador, es el porcentaje de sujetos que alcanzan una respuesta objetiva (es decir, respuesta parcial o mejor) utilizando las directrices del IWCLL actualizadas por el NCI-WG [Hallek, 2008]. La evaluación de la respuesta está prevista en los siguientes momentos :

    - Tras 3 ciclos de tratamiento con ofatumumab más bendamustina.
    - Tras 6 ciclos de tratamiento con ofatumumab más bendamustina.
    - Tras la última dosis, si no es después de 6 ciclos, de tratamiento con ofatumumab más bendamustina.
    2. Tasa de respuesta completa (TRC) determinada por el investigador, utilizando las directrices del IWCLL actualizadas por el NCI-WG [Hallek, 2008], con y sin TC.
    3. Supervivencia libre de progresión (SLP)
    4. Supervivencia global (SG)
    5. Tiempo hasta la respuesta y duración de la misma.
    6. Tiempo hasta la progresión y tiempo hasta el siguiente tratamiento.
    7. Incidencia y gravedad de acontecimientos adversos.
    8. Incidencia y gravedad de acontecimientos adversos graves.
    9. Incidencia y gravedad de reacciones a la infusión.
    10. Frecuencia de transfusiones.
    11. Incidencia de anemia hemolítica autoinmune (AHAI)
    12. Desarrollo de anticuerpos antihumanos-humanos (HAHA).
    13. Incidencia de infecciones y mielosupresión (anemia, neutropenia, trombocitopenia) de Grados 3 y 4 .
    14. Cambio en los niveles de células B.
    15. Cambio en la cantidad de IgG, IgA, IgM.
    16 .Mejora del estado funcional ECOG (Eastern Cooperative Oncology Group).
    17. Mejora de los síntomas constitucionales.
    18. Mejora de la fatiga.
    19. Enfermedad mínima residual (EMR) en los sujetos que alcancen RC, determinada por citometría de flujo.
    20. Citogenética mediante hibridación in situ fluorescente (FISH).
    21. ?2 microglobulina.
    22. Estado mutacional IgVH, consumo de VH3-21.
    23. ZAP70.
    E.5.2.1Timepoint(s) of evaluation of this end point
    As above and at the completion of the study (Jun-2016)
    Igual que el anterior y en la finalización del estudio (junio-2016)
    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 No
    E.6.7Pharmacodynamic No
    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Belgium
    Czech Republic
    Germany
    Greece
    Italy
    Poland
    Russian Federation
    Spain
    United States
    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
    LSLV will be the end of 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 years4
    E.8.9.1In the Member State concerned months7
    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 months7
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state11
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 62
    F.4.2.2In the whole clinical trial 80
    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)
    As per protocol
    Lo que se indica en el protocolo.
    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 Decision2012-03-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-12
    P. End of Trial
    P.End of Trial StatusOngoing
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