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    Summary
    EudraCT Number:2020-003908-14
    Sponsor's Protocol Code Number:M-2020-371
    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:2021-09-01
    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 number2020-003908-14
    A.3Full title of the trial
    A pivotal Phase II randomised, multi-centre, open-label study to evaluate the efficacy and safety of MB-CART2019.1 compared to standard of care therapy in participants with relapsed/refractory diffuse large B-cell lymphoma (R-R DLBCL), who are not eligible for high-dose chemotherapy and autologous stem cell transplantation
    Estudio fundamental de fase II, aleatorizado, multicéntrico y sin enmascaramiento para evaluar la eficacia y la seguridad de MB-CART2019.1 en comparación con el tratamiento de referencia en participantes con linfoma difuso de linfocitos B grandes recidivante/resistente (LDLBG R-R) que no son aptos para recibir quimioterapia de dosis altas ni autotrasplantes de células progenitoras
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate efficacy and safety of MB-CART2019.1 compared with usual medication for patients with diffuse large B-cell lymphoma
    Un estudio para evaluar la eficacia y seguridad de MB-CART2019.1 en comparación con la medicación habitual en pacientes con linfoma difuso de células B grandes
    A.3.2Name or abbreviated title of the trial where available
    DALY 2-EU
    A.4.1Sponsor's protocol code numberM-2020-371
    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 SponsorMiltenyi Biomedicine GmbH
    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 supportMiltenyi Biomedicine GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMiltenyi Biomedicine GmbH
    B.5.2Functional name of contact pointDirector Clinical Development
    B.5.3 Address:
    B.5.3.1Street AddressFriedrich-Ebert-Straße 68
    B.5.3.2Town/ cityBergisch Gladbach
    B.5.3.3Post code51429
    B.5.3.4CountryGermany
    B.5.4Telephone number+49220483066694
    B.5.5Fax number+49220483066699
    B.5.6E-mailsilke.holtkamp@miltenyi.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 nameMB-CART2019.1
    D.3.4Pharmaceutical form 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 INNAutologous CD20-CD19 CAR transduced CD4/CD8 enriched T cells
    D.3.9.2Current sponsor codeMB-CART2019.1
    D.3.9.3Other descriptive nameAUTOLOGOUS T CELLS TRANSDUCED WITH LENTIVIRAL VECTOR CONTAINING A CHIMERIC ANTIGEN RECEPTOR DIRECTED AGAINST CD19
    D.3.9.4EV Substance CodeSUB176601
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number2.5
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    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 GEMCITABINA HIKMA
    D.2.1.1.2Name of the Marketing Authorisation holderHikma Farmaceutica (Portugal), S.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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.3.4Pharmaceutical form Powder 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 INNGEMCITABINE HYDROCHLORIDE
    D.3.9.1CAS number 95058-81-4
    D.3.9.4EV Substance CodeSUB02324MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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.IMP: 3
    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 Truxima 500 mg concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderCelltrion Healthcare Hungary Kft.
    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.3.4Pharmaceutical 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 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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibody
    D.IMP: 4
    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 Oxaliplatin 5mg/ml concentrate for Solution for Infusion
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    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 nameOxaliplatin
    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 INNOXALIPLATIN
    D.3.9.1CAS number 61825-94-3
    D.3.9.4EV Substance CodeSUB09490MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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.IMP: 5
    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 Polivy 140 mg powder for concentrate for solution for infusion
    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 namePolatuzumab vedotin
    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 INNPOLATUZUMAB VEDOTIN
    D.3.9.1CAS number 1313206-42-6
    D.3.9.4EV Substance CodeSUB177827
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibody
    D.IMP: 6
    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 Bendamustine hydrochloride Accord 2.5 mg/ ml Powder for concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    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 hydrochloride
    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.3.9.4EV 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
    Relapsed/refractory diffuse large B cell lymphoma (R-R DLBCL)
    Linfoma difuso de linfocitos B grandes recidivante/resistente (LDLBG R-R)
    E.1.1.1Medical condition in easily understood language
    Diffuse large B cell lymphoma (DLBCL)
    Linfoma difuso de linfocitos B grandes (LDLBG)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10003903
    E.1.2Term B-cell lymphoma refractory
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10003902
    E.1.2Term B-cell lymphoma recurrent
    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 is to determine superiority of MB-CART2019.1 treatment compared to standard-of-care (SoC) therapy with R-GemOx (rituximab, gemcitabine and oxaliplatin) with respect to progression-free survival in second-line therapy in participants with R-R DLBCL, who are non-eligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT).
    El objetivo principal es determinar la superioridad del tratamiento con MB-CART2019.1 en comparación con el tratamiento de referencia con R-GemOx (rituximab, gemcitabina y oxaliplatino) con respecto a la supervivencia sin progresión en el tratamiento de segunda línea en participantes con LDLBG R-R que no son aptos para recibir quimioterapia de dosis altas ni autotrasplantes de células progenitoras (ATCP
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of MB-CART2019.1 compared to SoC therapy.
    • To evaluate the safety and toxicity of MB-CART2019.1 compared to SoC therapy.
    • To evaluate changes in health-related quality of life (HRQoL) and lymphoma symptoms of participants receiving MB-CART2019.1 compared to SoC therapy.
    •To evaluate the humoral immunogenicity against MB-CART2019.1.
    • Evaluar la eficacia de MB-CART2019.1 en comparación con el tratamiento de referencia.
    • Evaluar la seguridad y la toxicidad de MB-CART2019.1 en comparación con el tratamiento de referencia.
    • Evaluar los cambios en la calidad de vida relacionada con la salud (CVRS) y los síntomas del linfoma de los participantes que reciben MB-CART2019.1 en comparación con el tratamiento de referencia.
    • Evaluar la inmunogenia humoral frente a MB-CART2019.1.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically proven DLBCL and associated subtypes, according to the World Health Organisation (WHO) 2016 classification including:
    • DLBCL not otherwise specified (NOS).
    • High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double hit lymphoma/triple hit lymphoma).
    • High-grade BCL, NOS.
    • Primary (thymic) large mediastinal BCL.
    • Disease transformed from an earlier diagnosis of low-grade lymphoma (e.g. an indolent pathology such as follicular lymphoma, marginal zone lymphoma) into DLBCL with DLBCL disease progression subsequent to DLBCL directed systemic treatment.
    2. Relapsed or refractory disease after first-line chemoimmunotherapy:
    • Refractory disease is defined as no CR to first-line therapy.
    - PD as best response after at least 4 full cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone) cycles as first-line therapy.
    - Stable disease (SD) after 6 R-CHOP cycles as first-line therapy.
    - PR as best response after at least 6 R-CHOP cycles and biopsy-proven disease progression (except where prohibited due to comorbidities) within ≤ 12 months from the completion of the first-line therapy.
    • Relapsed disease defined as complete remission to a first-line therapy followed by biopsy-proven disease progression (except where prohibited due to comorbidities) within ≤ 12 months from the completion of the first-line therapy.
    3. Participants must have received adequate first-line therapy containing at least the combination of an anthracycline-based regimen and rituximab (anti-CD20 monoclonal antibody). Local therapies (e.g. radiotherapies) will not be considered as line of therapy if performed during the same line of treatment.
    4. Archival paraffin-embedded tumour tissue acquired ≤ 3 years prior to screening for central pathology review to confirm DLBCL diagnosis and for analysis of CD20/CD19 expression must be made available for participation in this study. If archival paraffin-embedded tumour tissue is not available, fresh tumour tissue sample (preferred) or core-needle biopsy for this protocol must be made available.
    5. Participants deemed ineligible to receive HDC followed by ASCT based on the treating physician’s assessment and meeting the following criteria:
    • Age ≥ 18 years and
    - Prior ASCT (as first-line consolidation) or
    - Haematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) > 3.
    • Age ≥ 65 years and 1 of the criteria below:
    - Prior ASCT (as first-line consolidation), or
    - Comorbidities as assessed by an HCT-CI score > 3, or
    - Impaired cardiac function (left ventricular ejection fraction (LVEF) < 50%), or
    - Impaired renal function (creatinine clearance [CrCl] < 60 mL/min) as determined by the MDRD
    (Modification of Diet in Renal Disease) formular, or
    - Impaired pulmonary function (diffusing capacity for carbon monoxide or forced expiratory volume in 1 second of 66% to 80%) or dyspnoea on slight activity, or
    - Eastern Cooperative Oncology Group (ECOG) performance status > 1.
    Documentation of the reason for ineligibility for ASCT must be present in the participant’s source data.
    In addition, all participants must fulfil the following criteria:
    6. Age ≥ 18 years.
    7. Measurable disease according to Lugano criteria. The lesion must be positive on a positron emission tomography scan.
    8. Estimated life expectancy of > 3 months for other reasons than the primary disease.
    9. Woman of childbearing potential (WOCBP) must agree to use highly effective contraceptive measures (Pearl index < 1) or practice true sexual abstinence from any heterosexual intercourse (True abstinence is only acceptable if it is in line with the preferred and usual life style of the participant.) or must have a vasectomised partner as the sole sexual partner (The vasectomised partner must have received medical assessment of the surgical success.) for at least 1 month before the study start, during the study and in the 12 months following the last dose of study treatment. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Highly effective methods of contraception include hormonal contraceptives (oral, intravaginal, transdermal, injectable, implantable) and intrauterine devices or systems (e.g. hormonal and non-hormonal) and bilateral tubal occlusion. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. WOCBP must refrain from egg donation throughout the study until 12 months after the last dose of study treatment. WOCBP must refrain from egg donation throughout the study until 12 months after the last dose of study treatment.

    FOR FULL LIST OF INCLUSION CRITERIA PLEASE REFER TO THE STUDY PROTOCOL
    1. LDLBG confirmado histológicamente y subtipos asociados, conforme a la clasificación de 2016 de la Organización Mundial de la Salud (OMS), incluidos:
    • LDLBG sin especificar.
    • Linfoma de linfocitos B de gran malignidad (LLBGM) con reordenamiento de los genes MYC y BCL2 y/o BCL6 con histología de LDLBG (linfomas con mutación doble/triple).
    • LLBGM sin especificar.
    • Linfoma primario mediastínico (tímico) de linfocitos B grandes.
    • Enfermedad transformada desde un diagnóstico anterior de linfoma de escasa malignidad (p. ej., una patología poco activa como linfoma folicular, linfoma de la zona marginal) a LDLBG con progresión de la enfermedad posterior a un tratamiento sistémico dirigido al LDLBG.
    2. Enfermedad recidivante o resistente después de una quimioinmunoterapia de primera línea:
    • «Enfermedad resistente» se define como la ausencia de RC a un tratamiento de primera línea.
     PE como mejor respuesta después de un mínimo de 4 ciclos completos de R-CHOP (rituximab, ciclofosfamida, hidroxidaunorrubicina, oncovin y prednisona) como tratamiento de primera línea.
     Enfermedad estable (EE) después de 6 ciclos de R-CHOP como tratamiento de primera línea.
     RP como mejor respuesta después de un mínimo de 6 ciclos de R-CHOP y progresión de la enfermedad confirmada mediante biopsia (salvo cuando esté contraindicada debido a enfermedades concomitantes) en un plazo ≤12 meses desde la finalización del tratamiento de primera línea.
    • «Enfermedad recidivante» se define como remisión completa en un tratamiento de primera línea seguida de progresión de la enfermedad confirmada mediante biopsia (salvo cuando esté contraindicada debido a enfermedades concomitantes) en un plazo ≤12 meses desde la finalización del tratamiento de primera línea.
    3. Los participantes deben haber recibido un tratamiento de primera línea adecuado que contenga como mínimo la combinación de una pauta basada en antraciclina y rituximab (anticuerpo monoclonal anti-CD20). Los tratamientos localizados (p. ej., radioterapias) no se considerarán línea de tratamiento si tienen lugar durante la misma línea de tratamiento.
    4. Para participar en este estudio debe ponerse a disposición tejido tumoral de archivo incluido en parafina obtenido ≤3 años antes de la selección para la revisión anatomopatológica central que confirme el diagnóstico de LDLBG y para los análisis de la expresión de CD20/CD19. Si no se dispone de tejido tumoral de archivo incluido en parafina, para este protocolo deberá ponerse a disposición una muestra de tejido tumoral fresco (preferido) o una biopsia con aguja gruesa.
    5. Participantes que no se consideren aptos para recibir QDA seguido de ATCP según la evaluación del médico responsable y cumplan los siguientes criterios:
    • Edad ≥18 años y
     ATCP anterior (como consolidación de primera línea) o
     puntuación >3 en el índice de enfermedades concomitantes específico para trasplantes de células hematopoyéticas (HCT-CI, Haematopoietic Cell Transplantation-specific Comorbidity Index).
    • Edad ≥65 años y uno de los siguientes criterios:
     ATCP anterior (como consolidación de primera línea) o
     enfermedades concomitantes según lo evaluado por una puntuación >3 en el HCT-CI, o
     insuficiencia cardiaca (fracción de expulsión del ventrículo izquierdo [FEVI] <50%), o
     insuficiencia renal (aclaramiento de creatinina [ACr] <60 ml/min) según lo determinado mediante la fórmula de modificación de la dieta en las nefropatías (MDRD, Modification of Diet in Renal Disease), o
     insuficiencia pulmonar (capacidad de difusión de monóxido de carbono o volumen espiratorio máximo [VEM] en un segundo entre el 66% y el 80%) o disnea al realizar una actividad ligera, o
     estado funcional >1 según el Grupo Oncológico Cooperativo de la Costa Este de los EE. UU. (ECOG, Eastern Cooperative Oncology Group).
    Los datos fuente del participante deben incluir documentación que demuestre el motivo de no ser apto para un ATCP.
    Además, todos los participantes deben cumplir los siguientes criterios:
    6. Edad ≥18 años.
    7. Enfermedad mensurable según los criterios de Lugano. La lesión debe ser visible en una tomografía por emisión de positrones.
    8. Esperanza de vida estimada >3 meses por otros motivos distintos que la enfermedad principal.

    PARA OBTENER LA LISTA COMPLETA DE CRITERIOS DE INCLUSIÓN CONSULTE EL PROTOCOLO DE ESTUDIO
    E.4Principal exclusion criteria
    1. Contraindications for R-GemOx and BR plus polatuzumab vedotin as judged by the treating physician.
    2. Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy.
    3. ECOG performance status > 2.
    4. Absolute neutrophil count < 1,000/µL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy required for screening).
    5. Platelet count < 50,000/µL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy required for screening).
    6. Absolute lymphocyte count < 100/µL.
    7. Participants who have CNS lymphoma involvement in present or past medical history.
    8. Known history of infection with human immunodeficiency virus or active infection with hepatitis B (hepatitis B surface antigen positive).
    9. Known history of infection with hepatitis C virus unless treated and confirmed to be polymerase chain reaction negative.
    10. Active infection with SARS-CoV-2.
    11. Known history or evidence of severely immunocompromised state; i.e. corticosteroid treatment > 10 mg/day for more than 6 months.
    12. Has received vaccination with live virus vaccines within 6 weeks prior to randomisation.
    13. Prior CD19 targeted therapy
    14. Known history or presence of seizure activities or on active antiseizure medications within the previous 12 months.
    15. Presence of CNS disease that, in the judgement of the investigator, may impair the ability to evaluate neurotoxicity.
    16. Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory disease.
    17. Known history or presence of cerebral vascular accident (CVA) within 12 months prior to randomisation. Note: In case of history of CVA > 12 months prior to leukapheresis, then the participant must not have any unstable or life-threatening neurological deficits.
    18. Participants with Richter's transformation or Richter's syndrome.
    19. Participants who are concurrently on any other experimental treatments or during the previous 4 weeks or 5-half-lives.
    20. Clinical heart failure with New York Heart Association class ≥ 2 or LVEF < 30%.
    21. Resting peripheral oxygen saturation < 90% on room air.
    22. Liver dysfunction as indicated by total bilirubin, aspartate aminotransferase and/or alanine aminotransferase > 5 × institutional upper limit of normal (ULN)
    23. Serum creatinine ≥ 2.0 × ULN or CrCl < 30 mL/min calculated according to the modified formula of MDRD.
    24. Pregnant or breast-feeding woman.
    25. Prior history of malignancies other than DLBCL, unless the participant has been free of the disease for ≥ 3 years prior to screening. Exceptions to the ≥ 3-year time limit include history of the following:
    • Basal cell carcinoma of the skin.
    • Squamous cell carcinoma of the skin.
    • Carcinoma in situ of the cervix.
    • Carcinoma in situ of the breast.
    • Carcinoma in situ of the bladder.
    • Incidental histological finding of untreated localized (T1a or T1b) prostate cancer under surveillance .
    26. History of severe immediate hypersensitivity reaction against any drug or its ingredients/impurities that is scheduled to be given during study participation e.g. as part of the mandatory lymphodepletion protocol, premedication for infusion, or rescue medication/salvage therapies for treatment-related toxicities.
    27. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
    28. Refusal to participate in CAR T long-term follow-up (LTFU).
    1. Contraindicaciones para recibir R-GemOx y BR más polatuzumab vedotina, según el criterio del médico responsable.
    2. Tratamiento previo con receptores de antígenos quiméricos u otros tratamientos con linfocitos T genomodificados.
    3. Estado funcional del ECOG >2.
    4. Recuento absoluto de neutrófilos <1000/µl (salvo que sea secundaria a afectación de la médula ósea por el LDLBG, confirmado en la biopsia de médula ósea requerida para la selección).
    5. Recuento de plaquetas <50 000/µl (salvo que sea secundaria a afectación de la médula ósea por el LDLBG, confirmado en la biopsia de médula ósea requerida para la selección).
    6. Recuento absoluto de linfocitos <100/µl.
    7. Participantes con afectación del linfoma en el SNC en la anamnesis actual o los antecedentes médicos.
    8. Antecedentes conocidos de infección por el virus de la inmunodeficiencia humana o infección activa por el virus de la hepatitis B (positiva al antígeno de superficie del virus de la hepatitis B).
    9. Antecedentes conocidos de infección por el virus de la hepatitis C, salvo que se haya tratado y confirmado con un resultado negativo en una reacción en cadena de la polimerasa.
    10. Infección activa por el SARS-CoV-2.
    11. Antecedentes conocidos o signos de estado gravemente inmunodeficiente; es decir, tratamiento con corticoesteroides >10 mg/día durante más de 6 meses.
    12. Haber recibido una vacuna con virus vivos durante las 6 semanas anteriores a la aleatorización.
    13. Tratamiento previo dirigido a CD19.
    14. Antecedentes conocidos o presencia de actividad convulsiva o estar recibiendo medicamentos anticonvulsivos activos durante los 12 meses anteriores.
    15. Presencia de enfermedad en el SNC que, a criterio del investigador, podría dificultar la capacidad de evaluar la neurotoxicidad.
    16. Antecedentes conocidos o presencia de enfermedad autoinmunitaria en el SNC, como esclerosis múltiple, neuritis óptica u otra enfermedad inmunitaria o inflamatoria.
    17. Antecedentes conocidos o presencia de accidente cerebrovascular (ACV) durante los 12 meses anteriores a la aleatorización.
    Nota: en caso de antecedentes de ACV >12 meses antes de la leucocitaféresis, el participante no debe haber presentado ningún déficit neurológico inestable o potencialmente mortal.
    18. Participantes con transformación o síndrome de Richter.
    19. Participantes que reciben simultáneamente cualquier otro tratamiento experimental o que lo recibieron durante las 5 semividas o 4 semanas anteriores.
    20. Insuficiencia cardiaca clínica de clase ≥2 según la Asociación Neoyorquina de Cardiología (NYHA, New York Heart Association) o FEVI <30 %.
    21. Saturación periférica de oxígeno en reposo <90% con aire ambiente.
    22. Insuficiencia hepática según lo indicado por unos valores de bilirrubina total, aspartato aminotransferasa y/o alanina aminotransferasa >5 veces el límite superior de la normalidad (LSN).
    23. Creatinina sérica ≥2,0 veces el LSN o ACr <30 ml/min, según lo calculado con la fórmula modificada de MDRD.
    24. Mujer embarazada o en periodo de lactancia.
    25. Antecedentes de neoplasias malignas distintas del LDLBG, salvo que el participante no haya presentado enfermedad durante ≥3 años antes de la selección. Son excepciones al periodo ≥3 años los antecedentes de:
    • Carcinoma basocelular cutáneo.
    • Carcinoma epidermoide cutáneo.
    • Carcinoma de cuello uterino localizado.
    • Carcinoma de mama localizado.
    • Carcinoma de vejiga localizado.
    • Hallazgos histológicos accidentales de cáncer de próstata (T1a o T1b) localizado, sin tratar y bajo vigilancia.
    26. Antecedentes de reacción de hipersensibilidad inmediata y grave ante cualquier fármaco, o sus ingredientes/impurezas, cuya administración esté prevista durante la participación en el estudio, p. ej., como parte del protocolo obligatorio del tratamiento productor de linfopenia, la premedicación para la infusión o la medicación de rescate para toxicidades relacionadas con el tratamiento.
    27. Cualquier afección médica que pueda interferir con la evaluación de la seguridad o la eficacia del tratamiento del estudio.
    28. Negativa a participar en el seguimiento a largo plazo (SLP) de T-CAR.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS), defined as the time between the date of randomisation and the date of objective disease progression or death of any cause, whichever occurs first, based on Independent Review Committee (IRC) assessment.
    Supervivencia sin progresión (SSP), definida como el tiempo que transcurre entre la fecha de la aleatorización y la fecha de la progresión objetiva de la enfermedad o de la muerte por cualquier causa, lo que suceda primero, según la evaluación del comité de revisión independiente (CRI).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The time between the date of randomisation and the date of objective disease progression or death of any cause, whichever occurs first, based on Independent Review Committee (IRC) assessment.
    El tiempo que transcurre entre la fecha de la aleatorización y la fecha de la progresión objetiva de la enfermedad o de la muerte por cualquier causa, lo que suceda primero, según la evaluación del comité de revisión independiente (CRI).
    E.5.2Secondary end point(s)
    Key Efficacy Endpoints:
    1. Event-free-survival (EFS; progression of disease, start of new anti-cancer treatment, relapse or death of any cause), defined as the time between the date of randomisation and the date of the event.
    2. Best complete response rate (BCRR), defined as the proportion of participants with at least one complete response assessment, based on IRC assessment.
    3. Duration of complete response, defined as the time between the date of a first complete response (CR) and the date of assessment of relapse or the date of death due to DLBCL, whichever occurs first, based on IRC assessment.
    4. Overall survival (OS), defined as time between the date of randomisation and the date of death of any cause.
    Other Secondary Endpoints:
    • PFS rates at 6 and 12 months, based on investigator and/or IRC assessment.
    • BCRR, defined as the proportion of participants with at least one CR assessment, based on investigator assessment.
    • Duration of complete response, defined as the time between the date of a first CR and the date of assessment of relapse or the date of death due to
    DLBCL, whichever occurs first, based on investigator assessment.
    • Duration of response (DOR), defined as the time between the date of a first objective response (CR/partial response [PR]) and the date of assessment of relapse or the date of death due to DLBCL, whichever occurs first, based on investigator and/or IRC assessment.
    • Time to objective response (TTR), defined as the time between the date of randomisation and the date of a first objective response (CR/PR), based on investigator and/or IRC assessment.
    • Objective response rate (ORR), defined as the proportion of participants with either a CR or PR, based on investigator and/or IRC assessment.
    • Complete response rate (CRR), defined as the proportion of participants with a CR, based on investigator and/or IRC assessment.
    • Best objective response (BOR), defined as the best objective response in the time between the date of randomisation and the date of the occurrence of progressive disease (PD) or relapse, the start of new anticancer therapy or the date of death from any cause, whichever occurs first, based on investigator and/or IRC assessment.
    • Change in B symptoms from baseline (fever [> 38°C], night sweats and/or unintentional weight loss [≥ 10% of body weight]).
    • Changes in HRQoL and lymphoma symptoms.
    In MB-CART2019.1 arm only:
    • Persistence of MB-CART2019.1 and phenotype and immune cell compositions, based on flow cytometry analyses and qPCR.
    • Types and levels of cytokines (including sIL-2R, IL-6, IL-10, IL-15, IFN-γ and TNFα).
    • Anti-MB-CART2019.1 antibody.
    Safety Endpoints:
    • Type, frequency and severity of adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs).
    • Hospital days within 7 month after randomisation.
    • Intensive care unit (ICU) admission days within 7 months after randomisation.
    • Use of tocilizumab and/or high-dose steroids.
    • Need for transfusions, prophylactic antimicrobial therapy and gamma globulin substitution.
    Criterios clave de valoración de la eficacia:
    1. Supervivencia sin acontecimientos (SSA; progresión de la enfermedad, inicio de un nuevo tratamiento antineoplásico, recidiva o muerte por cualquier causa), definida como el tiempo que transcurre entre la fecha de la aleatorización y la fecha del acontecimiento.
    2. Mejor tasa de respuestas completas (MTRC), definida como la proporción de participantes con al menos una evaluación de respuesta completa, según la evaluación del CRI.
    3. Duración de la respuesta completa, definida como el tiempo que transcurre entre la fecha de una primera respuesta completa (RC) y la fecha de la evaluación de la recidiva o la fecha de la muerte por LDLBG, lo que suceda primero, según la evaluación del CRI.
    4. Supervivencia global (SG), definida como el tiempo que transcurre entre la fecha de la aleatorización y la fecha de la muerte por cualquier causa.

    Otros criterios secundarios de valoración:
    • Tasas de SSP a los 6 y 12 meses, según la evaluación del investigador o el CRI.
    • MTRC, definida como la proporción de participantes con al menos una evaluación de RC, según la evaluación del investigador.
    • Duración de la respuesta completa, definida como el tiempo que transcurre entre la fecha de una primera RC y la fecha de la evaluación de la recidiva o la fecha de la muerte por LDLBG, lo que suceda primero, según la evaluación del investigador.
    • Duración de la respuesta (DR), definida como el tiempo que transcurre entre la fecha de una primera respuesta objetiva (RC/respuesta parcial [RP]) y la fecha de la evaluación de la recidiva o la fecha de la muerte por LDLBG, lo que suceda primero, según la evaluación del investigador o el CRI.
    • Tiempo hasta la respuesta objetiva (THRO), definido como el tiempo que transcurre entre la fecha de la aleatorización y la fecha de una primera respuesta objetiva (RC/RP), según la evaluación del investigador o el CRI.
    • Tasa de respuestas objetivas (TRO), definida como la proporción de participantes con una RC o una RP, según la evaluación del investigador o el CRI.
    • Tasa de respuestas completas (TRC), definida como la proporción de participantes con una RC, según la evaluación del investigador o el CRI.
    • Mejor respuesta objetiva (MRO), definida como la mejor respuesta objetiva observada en el tiempo que transcurre entre la fecha de la aleatorización y la fecha en que se produce la progresión de la enfermedad (PE) o la recidiva, el inicio de un nuevo tratamiento antineoplásico o la fecha de la muerte por cualquier causa, lo que suceda primero, según la evaluación del investigador o el CRI.
    • Cambio en los síntomas B respecto al inicio (fiebre [>38 °C], sudores nocturnos o pérdida de peso involuntaria [≥10% del peso corporal]).
    • Cambios en la CVRS y los síntomas del linfoma.
    Únicamente en el grupo tratado con MB-CART2019.1:
    • Persistencia de MB-CART2019.1 y composición fenotípica y de las células inmunitarias, a partir de análisis de citometría de flujo y de la reacción en cadena de la polimerasa cuantitativa (RCPc).
    • Tipos y niveles de citocinas (incluidas sIL-2R, IL-6, IL-10, IL-15, IFN- y FNT).
    • Anticuerpos anti-MB-CART2019.1.
    Criterios de valoración de la seguridad:
    • Tipo, frecuencia e intensidad de los acontecimientos adversos (AA), acontecimientos adversos graves (AAG) y acontecimientos adversos de interés especial (AAIE).
    • Días de hospitalización durante los 7 meses posteriores a la aleatorización.
    • Días de ingreso en la unidad de cuidados intensivos (UCI) durante los 7 meses posteriores a la aleatorización.
    • Uso de tocilizumab o corticoides a dosis altas.
    • Necesidad de transfusiones, tratamiento antimicrobiano profiláctico y reposición de gammaglobulina.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. The time between the date of randomisation and the date of the event.
    2. The proportion of participants with at least one complete response assessment, based on IRC assessment.
    3. The time between the date of a first complete response (CR) and the date of assessment of relapse or the date of death due to DLBCL, whichever occurs first, based on IRC assessment.
    4. The time between the date of randomisation and the date of death of any cause.
    For other Secondary Endpoints:
    • PFS rates at 6 and 12 months, based on investigator and/or IRC assessment.
    • The proportion of participants with at least one CR assessment, based on investigator assessment
    FOR FULL LIST OF TIMEPOINTS OF EVALUATION PLEASE REFER TO THE STUDY PROTOCOL
    1. El tiempo que transcurre entre la fecha de la aleatorización y la fecha del acontecimiento.
    2. La proporción de participantes con al menos una evaluación de respuesta completa, según la evaluación del CRI.
    3. El tiempo que transcurre entre la fecha de una primera respuesta completa (RC) y la fecha de la evaluación de la recidiva o la fecha de la muerte por LDLBG, lo que suceda primero, según la evaluación del CRI.
    4. El tiempo que transcurre entre la fecha de la aleatorización y la fecha de la muerte por cualquier causa.
    Otros criterios secundarios de valoración:
    • Tasas de SSP a los 6 y 12 meses, según la evaluación del investigador o el CRI.
    • La proporción de participantes con al menos una evaluación de RC, según la evaluación del investigador.
    VER PROTOCOLO ESTUDIO
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others 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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee 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
    LPLV
    Ultima visita del ultimo 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 days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    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: 117
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 51
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 168
    F.4.2.2In the whole clinical trial 168
    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)
    Up to 2 years after dosing regular long-term follow-up visits will be performed. The treating physician assesses the post treatment options of the individual patient; e.g. possibility to participate in further investigational trials and/or treatment on a named patient basis.
    After completion of the long-term follow-up, patients will be rolled over to a subsequent follow up trial for further 13 years.
    Hasta 2 años después de la dosificación, se realizarán visitas regulares de seguimiento a largo plazo. El médico tratante evalúa las opciones posteriores al tratamiento del paciente individual; p.ej. posibilidad de participar en más ensayos de investigación y / o tratamiento en base a un paciente designado.
    Una vez completado el seguimiento a largo plazo, los pacientes pasarán a un ensayo de seguimiento posterior durante 13 años más.
    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 Decision2021-05-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-16
    P. End of Trial
    P.End of Trial StatusOngoing
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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