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    Summary
    EudraCT Number:2018-004223-36
    Sponsor's Protocol Code Number:RI-01-006
    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:2019-05-27
    Trial 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 number2018-004223-36
    A.3Full title of the trial
    A Randomised, Double-blind, Parallel-group, Phase III Study to Compare the Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) with MabThera® in Subjects with Previously Untreated, Stage II-IV, Cluster of Differentiation (CD)20-Positive, Low Tumour Burden Follicular Lymphoma
    Estudio de fase III, aleatorizado, en doble ciego y de grupos paralelos, para comparar la eficacia, seguridad e inmunogenia del biosimilar del rituximab que se propone (DRL_RI) frente a MabThera® en sujetos con linfoma folicular de baja carga tumoral, positivo para el cluster de diferenciación (CD)20, en estadio II-IV, no tratado previamente
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase III Study to Compare the Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) with MabThera® in Subjects with Previously Untreated Follicular Lymphoma
    Estudio de fase III para comparar la eficacia, seguridad e inmunogenia del biosimilar del rituximab que se propone (DRL_RI) frente a MabThera® en sujetos con linfoma folicular no tratado previamente.
    A.4.1Sponsor's protocol code numberRI-01-006
    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 SponsorDr. Reddy’s Laboratories S.A.
    B.1.3.4CountrySwitzerland
    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 supportDr. Reddy’s Laboratories S.A.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDr. Reddy’s Laboratories Ltd.
    B.5.2Functional name of contact pointDr. Sonica Sachdeva Batra
    B.5.3 Address:
    B.5.3.1Street AddressSurvey no. 47, Bachupally Village, Bachupally, Mandal
    B.5.3.2Town/ cityMedchal Malkajgiri District
    B.5.3.3Post code500 090
    B.5.3.4CountryIndia
    B.5.4Telephone number+914044644500
    B.5.6E-mailsonicabatra@drreddys.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 nameDr. Reddy’s rituximab
    D.3.2Product code DRL_RI
    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/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) 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 Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product 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/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) 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 Yes
    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
    Follicular Lymphoma
    Linfoma Folicular
    E.1.1.1Medical condition in easily understood language
    Follicular lymphoma is a type of blood cancer. It is the most common of the indolent (slow-growing) non-Hodgkin's lymphomas, and the second-most-common form of non-Hodgkin's lymphomas overall.
    El linfoma folicular es un tipo de cáncer sanguíneo. Es el más común de los linfomas no Hodgkin indolentes (de crecimiento lento) y la segunda forma más común de linfomas no Hodgkin, en general.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the current study is to demonstrate the equivalent efficacy of DRL_RI and MabThera® in subjects with cluster of differentiation (CD)20-positive, low tumour burden follicular lymphoma (LTB-FL) in the first-line treatment setting, as measured by overall response rate (ORR).
    Demostrar la equivalencia de la eficacia de DRL_RI y MabThera® en sujetos con LTB-FL positivo para el antígeno CD20 de los linfocitos B, en su medición mediante la ORR , evaluada de acuerdo con los criterios de respuesta publicados para el linfoma maligno
    E.2.2Secondary objectives of the trial
    ·To compare the progression-free survival (PFS), ORR at Week 12, overall survival (OS), and duration of response (DOR) of DRL_RI with MabThera® in subjects with CD20- positive, LTB-FL.
    ·To compare the safety, tolerability, and immunogenic ity of DRL_RI with MabThera® in subjects with CD20-positive, LTB-FL.
    .Comparar la supervivencia sin progresión (progression-free survival, PFS), la ORR en la Semana 12, la supervivencia global (overall survival, OS) y la duración de la respuesta (duration of response, DOR) con DRL_RI frente a MabThera® en sujetos con LTB-FL positivo para CD20.
    .Comparar la seguridad, tolerabilidad e inmunogenia de DRL_RI frente a MabThera® en sujetos con LTB-FL positivo para CD20.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed written informed consent.

    2. Male or female subjects aged ≥18 years of age.

    3. Histologically confirmed, Grade 1-3a, previously untreated, CD20-positive, LTB-FL as per Groupe D’Etude des Lymphomes Folliculaires (GELF) criteria. Subjects must have tissue available for the central pathology review, and a centrally-confirmed diagnosis prior to being randomised. Should a subject be eligible as per the central imaging review but not as per the Study Centre Review the subject will be considered eligible if confirmed both by the Investigator and the Medical Monitor. For any other disagreement in eligibility the subject will be considered ineligible.

    4. Ann Arbor Stage II to IV of histological Grade 1, 2, or 3a.

    5. ECOG status of 0 to 1.

    6. Low tumour burden follicular lymphoma defined as:
    · As per central radiological assessment, nodal or extranodal mass involvement with diameter measuring <7 cm
    · As per central radiological assessment, involvement of <3 nodal sites with diameter measuring >3 cm
    · Absence of systemic symptoms or B-symptoms* (asymptomatic)
    *B-symptoms defined as weight loss >10% within last 6 months, recurrent or continuous night sweats, intermittent or continuous fever recorded as axillary or oral temperature >38°C for at least 3 days
    · As per central radiological assessment, absence of splenomegaly (defined as spleen size higher than 16 cm by computed tomography [CT] scan)
    · Absence of risk of vital organ compression based on clinical finding
    · Absence of leukemic phase (leukemic phase defined as a count >5,000/µL of circulating tumour cells)
    · Absence of clinically significant cytopenias (defined as a platelet count of <100,000/µL, haemoglobin <10 g/dL, or absolute neutrophil count <1,500/µL)
    · Absence of clinically significant serous effusion based on clinical examination and CT scan
    · Serum LDH not higher than the upper limit of normal (ULN) by local laboratory.

    7. Subject has at least 1 measurable tumour mass in 2 dimensions as per central radiological assessment, and the mass must be:
    · Nodal lesion >15 mm in the longest dimension; or
    · Nodal lesion >10 mm to ≤15 mm in the longest dimension and >10 mm in the shortest dimension; or
    · Extranodal lesion with both long and short dimensions ≥10 mm.

    8. Creatinine clearance ≥45 mL/min as calculated by the Cockcroft-Gault method.

    9. Aspartate transaminase, alanine transaminase, alkaline phosphatase values ≤3 × ULN, total or conjugated bilirubin values ≤1.5 × ULN.

    10. Life expectancy ≥3 months.

    11. Able to comply with the study protocol.

    12. If female subject, then subject should be non-pregnant, non-lactating. Adequate contraception or post-menopausal/non-childbearing status. Women of childbearing potential must practice effective birth control for the duration of the study and for 12 months after the last study drug dose. For this same duration, male subjects participating in the study should avoid passing the semen to female partners during sexual intercourse.
    1. Firma del consentimiento informado por escrito.
    2. Varón o mujer de edad >/=18 años.
    3. LTB-FL positivo para CD20, confirmado histológicamente, de Grado 1-3a, no tratado previamente, según los criterios del Groupe D’Etude des Lymphomes Folliculaires (GELF). Deberá disponerse de tejido de los sujetos para su examen anatomopatológico central, y deberá disponerse también de su diagnóstico confirmado centralmente antes de la aleatorización. Si un sujeto fuera elegible según la revisión central de los estudios de diagnóstico por imagen pero no por la Study Centre Review, se considerará elegible si lo confirman el Investigador y el Monitor Médico. Ante cualquier otra discordancia en la elegibilidad, el sujeto se considerará no elegible.
    4. Estadio II a IV de Grado histológico 1, 2 o 3a de Ann Arbor
    5. Estado funcional del ECOG 0 o 1.
    6. Linfoma folicular de baja carga tumoral, lo que se define como:
    -En su evaluación radiológica central, masa ganglionar o extraganglionar de diámetro <7 cm
    -En su evaluación radiológica central, afectación de <3 áreas ganglionares de diámetro >3 cm
    -Ausencia de síntomas sistémicos o síntomas B* (asintomático)
    *Los síntomas B se definen como pérdida de peso >10% en los 6 últimos meses, sudoración nocturna recurrente o continua, fiebre (esto es, temperatura axilar u oral >38°C) intermitente o continua durante como mínimo 3 días
    -En su evaluación radiológica central, ausencia de esplenomegalia (definida como tamaño esplénico mayor de 16 cm mediante tomografía computarizada [computed tomography, CT])
    -Según los hallazgos clínicos, ausencia de riesgo de compresión de órgano vital
    -Ausencia de fase leucémica (la fase leucémica se define como células tumorales circulantes >5.000/µL)
    -Ausencia de citopenias clínicamente importantes (definidas como plaquetas<100.000/µL, hemoglobina <10 g/dL o recuento absoluto de neutrófilos <1.500/µL)
    -Ausencia de derrame seroso clínicamente importante según la exploración física y la tomografía computarizada
    -LDH en suero no mayor del límite superior de la normalidad (upper limit of normal, ULN) del laboratorio local.
    7. El sujeto presenta como mínimo 1 masa tumoral medible en 2 dimensiones (según la evaluación radiológica central) y la masa debe ser:
    -Lesión ganglionar >15 mm en su eje mayor; o
    -Lesión ganglionar >10 mm a </=15 mm en su eje mayor y >10 mm en su eje menor; o
    -Lesión extraganglionar con ambos ejes, mayor y menor, >/=10 mm.
    8. Aclaramiento de creatinina >/= 45 mL/min calculado según la fórmula de Cockcroft-Gault.
    9. Aspartato transaminasa, alanina transaminasa y fosfatasa alcalina </=3 × ULN, bilirrubina total o conjugada </=1,5 × ULN.
    10. Esperanza de vida >/=3 meses.
    11. Capacidad para cumplir con el protocolo del estudio.
    12. Si se trata de una mujer, no podrá estar embarazada ni practicando la lactancia natural. Deberá observar un método anticonceptivo adecuado o encontrarse en posmenopausia o no ser fértil. Las mujeres potencialmente fértiles deberán utilizar un método anticonceptivo efectivo a lo largo del estudio y los 12 meses siguientes a la última dosis del fármaco del estudio. Durante estos mismos plazos, los varones participantes del estudio deberán evitar inseminar a sus parejas en las relaciones sexuales.
    E.4Principal exclusion criteria
    1. Prior use of rituximab or any CD20 monoclonal antibody for any reason.

    2. Any contraindication to the use of rituximab.

    3. Any prior therapy for follicular lymphoma (including but not limited to chemotherapy, radiotherapy).

    4. Subjects who, in the opinion of the Investigator, require additional concomitant treatment for lymphoma.

    5. Evidence of histologic transformation to high grade lymphoma or diffuse large B-cell lymphoma.

    6. Known Central Nervous System (CNS) involvement by lymphoma. (Note: CNS imaging is not required unless clinically indicated).

    7. Subjects on chronic supra-substitutive doses (defined as doses in excess of 7.5 mg per day of prednis one or prednis one equivalent for a period longer than 3 weeks) of systemic glucocorticoids.

    8. Prior malignancy, other than non-melanoma skin cancer or intraepithelial cervical neoplasia, successfully treated more than 1 year before study inclusion.

    9. Subjects with any of the following: known seropositivity for or history of active viral infection with human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) positive or hepatitis B core antibody positive, hepatitis C virus (HCV) antibody positive.

    10. Subjects with active tuberculosis (TB). Subjects with evidence of latent TB or a history of TB must have completed treatment or have initiated treatment for at least 1 month before the first dose of study drug (Day 1). Tuberculosis testing (QuantiFERON®-TB Gold-in-Tube test - QFT-GIT or QuantiFERON®-TB Gold Plus) is requested only if it is required by local regulations or practice.

    11. Subjects who have received a live vaccine within last 3 months of the first administration of study drug.

    12. Subjects with an active uncontrolled infection requiring systemic treatment at Screening or history of documented recurrent clinically significant infection within 6 months of study inclusion (e.g., 2 or more viral, bacterial or fungal infections requiring in-patient treatment).

    13. Subjects with New York Heart Association (NYHA) class III or IV congestive heart failure or relevant arrhythmia or angina based on ECG with clinical judgment.

    14. Subjects with known hypersensitivity to rituximab or its excipients, or to proteins of murine or other foreign origin.

    15. History or presence of a medical condition or disease that in the Investigator's opinion would place the subject at an unacceptable risk for study participation.

    16. Participation in any clinical study or having taken any investigational therapy during the 2-month period immediately preceding administration of the first dose of study drug.

    17. Lactating or pregnant female.

    18. Women of childbearing potential who do not consent to use highly effective methods of birth control (e.g., sterilisation, or other non-hormonal forms of contraception) during treatment and for at least 12 months after the last administration of study drug. True abstinence periodic abstinence (e.g., calendar ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

    19. Subject has been previously enrolled and/or randomized in this study.

    20. Subject likely not to be available to complete all protocol required study visits or procedures.
    1. Uso previo, por cualquier razón, de rituximab o cualquier anticuerpo monoclonal frente a CD20.
    2. Cualquier contraindicación para el uso del rituximab.
    3. Todo tratamiento previo para el linfoma folicular (incluidas, entre otras, quimioterapia o radioterapia).
    4. Sujetos que, en opinión del Investigador, precisan tratamiento concomitante adicional para el linfoma.
    5. Evidencia de transformación histológica a linfoma de alto grado o a linfoma de células B grandes difuso.
    6. Afectación conocida del sistema nervioso central por el linfoma (Nota: no se precisan estudios de neuroimagen, salvo que exista indicación clínica).
    7. Sujetos en tratamiento crónico con glucocorticoides sistémicos a dosis superiores a las sustitutivas (lo que se define como dosis mayores de 7,5 mg al día de prednisona o de equivalente a prednisona durante un periodo superior a 3 semanas).
    8. Neoplasia maligna previa, a excepción del cáncer cutáneo de tipo no melanoma o de la neoplasia intraepitelial de cuello uterino tratados con éxito más de 1 año antes de la inclusión en el estudio.
    9. Sujetos con cualquiera de lo siguiente: seropositividad conocida o antecedente de infección viral activa por el virus de la inmunodeficiencia humana (human immunodeficiency virus, HIV), positividad del antígeno de superficie de la hepatitis B hepatitis B (HBsAg) o del anticuerpo core de la hepatitis B, o positividad del anticuerpo contra el virus de la hepatitis C (HCV).
    10. Sujetos con tuberculosis (TB) activa. Los sujetos con evidencia de TB latente o historia de TB deberán haber completado o iniciado el tratamiento pertinente como mínimo 1 mes antes de la primera dosis del fármaco del estudio (Día 1). Solo se precisará la práctica de una prueba de la tuberculosis (QuantiFERON®-TB Gold-in-Tube - QFT-GIT o QuantiFERON®-TB Gold Plus) si así lo exigieran las normas o la práctica locales.
    11. Sujetos que hayan recibido una vacuna de gérmenes vivos en el plazo de los 3 meses anteriores a la primera administración del fármaco del estudio.
    12. Sujetos con infección activa no controlada que precisa tratamiento sistémico en la Selección o antecedente documentado de infección clínicamente importante recurrente en el plazo de los 6 meses anteriores a la inclusión en el estudio (por ejemplo, dos o más infecciones víricas, bacterianas o fúngicas que hayan precisado tratamiento con paciente ingresado).
    13. Sujetos con insuficiencia cardíaca congestiva de clase III IV de la New York Heart Association (NYHA) o arritmia o angina importantes de acuerdo al ECG y al criterio clínico.
    14. Sujetos con hipersensibilidad conocida al rituximab o sus excipientes, o a las proteínas de origen murino u otro origen exógeno.
    15. Antecedente o presencia de proceso médico o enfermedad que, en opinión del Investigador, suponga para el sujeto un riesgo inaceptable como consecuencia de la participación en el estudio.
    16. Participación en un estudio clínico o recepción de un tratamiento en fase de investigación durante el periodo de los 2 meses inmediatamente anteriores a la administración de la primera dosis del fármaco del estudio.
    17. Mujeres lactantes o embarazadas.
    18. Mujeres potencialmente fértiles que no están de acuerdo en utilizar métodos anticonceptivos altamente efectivos (por ejemplo, esterilización u otras formas de anticoncepción no hormonales) durante el tratamiento y como mínimo los 12 meses siguientes a la última administración del fármaco del estudio. No se admiten como métodos anticonceptivos la abstinencia real, la abstinencia periódica (métodos de ovulación según calendario, sintotérmico y postovulación) ni el coito interrumpido.
    19. Sujeto que ya ha sido incluido y/o aleatorizado previamente en este estudio.
    20. Sujeto que no es probable que se encuentre disponible para acudir a todas las visitas o someterse a todos los procedimientos exigidos por el protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is ORR, defined as the proportion of subjects in each treatment group that achieve CR, CRu or PR at Month 7 (Week 28) based on central radiology review in accordance with the response criteria for malignant lymphoma (Cheson BD et al., 1999).
    El criterio de valoración principal es la ORR, definida como el porcentaje de sujetos de cada grupo de tratamiento que alcanza una respuesta completa (complete response, CR), respuesta completa no confirmada (unconfirmed complete response, CRu) o respuesta parcial (partial response, PR) en el Mes 7 (Semana 28), según la revisión radiológica central de acuerdo con los criterios de respuesta del linfoma maligno (Cheson BD et al., 1999).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the whole study.
    A lo largo de todo el estudio.
    E.5.2Secondary end point(s)
    · Progression-free survival defined as the time from date of randomisation to the date of documented progressive disease (PD) or death due to any cause.
    · Overall response rate at Week 12 based on central radiology review in accordance with published response criteria for malignant lymphoma (Cheson BD et al., 1999).
    · Overall survival defined as the time from date of randomisation to the date of death from any cause up to 52 weeks/End of Study (EOS).
    · Duration of response defined as the time from date of the first documentation of tumour response (CR, CRu or PR) to the date of first documentation of PD or to death due to any cause up to 52 weeks/EOS.
    · Adverse events, clinical laboratory values, vital signs, and electrocardiogram (ECG)
    · Anti-DRL_RI antibodies and their relationship with other outcome measures.
    -La supervivencia sin progresión, definida como el tiempo desde la fecha de aleatorización hasta la fecha de documentación de enfermedad progresiva (progressive disease, PD) o la muerte por cualquier causa.
    -La tasa de respuesta global en la Semana 12, según la revisión radiológica central de acuerdo con los criterios de respuesta publicados para el linfoma maligno (Cheson BD et al., 1999).
    -Supervivencia global, definida como el tiempo desde la fecha de la aleatorización hasta la fecha de la muerte por cualquier causa, hasta las 52 semanas/Fin del Estudio (End of Study, EOS).
    -Duración de la respuesta, definida como el tiempo desde la fecha de la primera documentación de respuesta del tumor (CR, CRu o PR) hasta la fecha de la primera documentación de PD o la muerte por cualquier causa, hasta las 52 semanas/Fin del Estudio.
    -Acontecimientos adversos (adverse events, AE), determinaciones de laboratorio, constantes vitales y electrocardiograma (ECG).
    -Anticuerpos anti-DRL_RI y su relación con otros parámetros del desenlace terapéutico.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the whole study.
    A lo largo de todo 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 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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    A lo largo de todo el estudio.
    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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA68
    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
    Belarus
    Bosnia and Herzegovina
    Bulgaria
    China
    Czech Republic
    Georgia
    Greece
    India
    Italy
    Korea, Republic of
    Poland
    Portugal
    Romania
    Russian Federation
    Serbia
    Spain
    Thailand
    Turkey
    Ukraine
    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
    LVLS
    Última visita último paciente
    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 months1
    E.8.9.1In the Member State concerned days18
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    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: 184
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 138
    F.4.2.2In the whole clinical trial 284
    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 study drug DRL_RI will not be available after the completion of the study. MabThera® can be procured from the market.
    El medicamento de estudio DRL_RI no estará disponible después de la finalización del estudio. MabThera® podrá adquirirse en el mercado
    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 Decision2019-05-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-30
    P. End of Trial
    P.End of Trial StatusOngoing
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