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    Summary
    EudraCT Number:2020-003908-14
    Sponsor's Protocol Code Number:M-2020-371
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-08-02
    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 ConcernedItaly - Italian Medicines Agency
    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
    Studio pivotale di Fase II, randomizzato, multicentrico, in aperto per valutare l’efficacia e la sicurezza di MB-CART2019.1 rispetto alla terapia dello standard di cura in partecipanti con linfoma diffuso a grandi cellule B recidivato/refrattario (R-R DLBCL) che non sono idonei alla chemioterapia ad alto dosaggio e al trapianto autologo di cellule staminali.
    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
    Uno studio per valutare l'efficacia e la sicurezza di MB-CART2019.1 rispetto ai farmaci abituali per i pazienti con linfoma diffuso a grandi cellule B
    A.3.2Name or abbreviated title of the trial where available
    DALY 2-EU
    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 number4922048306694
    B.5.5Fax number49220483066699
    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.3.2Product code [MB-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 INNLinfociti T CD4/CD8 autologhi arricchiti, trasdotti con CAR CD20-CD19
    D.3.9.2Current sponsor codeMB-CART2019.1
    D.3.9.4EV Substance CodeSUB176601
    D.3.10 Strength
    D.3.10.1Concentration unit µg/kg microgram(s)/kilogram
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number2
    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 Bendamustine hydrochloride Accord 2.5 mg/ ml polvere per concentrato per soluzione per infusione
    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.3.2Product code [Bendamustine 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 INNBENDAMUSTINA CLORIDRATO
    D.3.9.1CAS number 3543-75-7
    D.3.9.2Current sponsor codeBendamustina Cloridrato
    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
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 concentrato di soluzione per infusione
    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.3.1Product nameRituximab
    D.3.2Product code [Rituximab]
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.2Current sponsor codeRituximab
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 typeanticorpo monoclonale
    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 concentrato di soluzione per infusione
    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.3.2Product code [Oxaliplatin]
    D.3.4Pharmaceutical form Concentrate for solution for injection/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 INNOXALIPLATINO
    D.3.9.1CAS number 61825-94-3
    D.3.9.2Current sponsor codeOxaliplatino
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 polvere per concentrato per soluzione per infusione
    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.3.2Product code [Polatuzumab 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 INNPolatuzumav vedotin
    D.3.9.1CAS number 1313206-42-6
    D.3.9.2Current sponsor code1313206-42-6
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 typeANTICORPO MONOCLONALE
    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 GEMCITABINA HIKMA - 1 G POLVERE PER SOLUZIONE PER INFUSIONE 5 FLACONCINI IN VETRO
    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.3.1Product nameGEMCITABINA HIKMA
    D.3.2Product code [GEMCITABINA HIKMA]
    D.3.4Pharmaceutical form Powder for solution for injection/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 INNGEMCITABINA
    D.3.9.1CAS number 95058-81-4
    D.3.9.2Current sponsor codeGEMCITABINA
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 diffuso a grandi cellule B recidivante / refrattario (R-R DLBCL)
    E.1.1.1Medical condition in easily understood language
    Diffuse large B cell lymphoma (DLBCL)
    Linfoma diffuso a grandi cellule B (DLBCL)
    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 progressionfree 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).
    L’obiettivo primario è determinare la superiorità del trattamento MB-CART2019.1 rispetto alla terapia standard di cura (SoC) con R-GemOx (rituximab, gemcitabina e oxaliplatino) per quanto attiene alla sopravvivenza libera da progressione nella terapia di seconda linea in partecipanti con DLBCL R-R non idonei alla chemioterapia ad alta dose e al trapianto autologo di cellule staminali (ASCT).
    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.
    • Valutare l’efficacia di MB-CART2019.1 rispetto alla terapia SoC.
    • Valutare la sicurezza e la tossicità di MB-CART2019.1 rispetto alla terapia SoC.
    • Valutare i cambiamenti nella qualità della vita correlata alla salute (HRQoL) e nei sintomi del linfoma in partecipanti che ricevono MB-CART2019.1 rispetto alla terapia SoC.
    • Valutare l’immunogenicità umorale contro 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 andrituximab (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 (HCTCI) > 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
    FOR FULL LIST OF INCLUSION CRITERIA PLEASE REFER TO THE STUDY PROTOCOL
    1. DLBCL e sottotipi associati dimostrato istologicamente, in base alla classificazione 2016 dell’Organizzazione mondiale della sanità (OMS), inclusi:
    • DLBCL non altrimenti specificato (NOS);
    • linfoma a cellule B di grado elevato (HGBL) con riarrangiamenti di MYC e BCL2 e/o BCL6 con istologia DLBCL (linfoma double hit/triple hit);
    • BCL di grado elevato, NOS;
    • BCL primitivo del mediastino (timico) a grandi cellule;
    • malattia convertita da una diagnosi precedente di linfoma di basso grado (es. una patologia indolente come linfoma follicolare, linfoma a zona marginale) in DLBCL con una progressione della malattia DLBCL successiva al trattamento sistemico diretto per DLBC;
    2. Malattia recidivante o refrattaria dopo chemioimmunoterapia di prima linea:
    • per malattia refrattaria s’intende nessuna CR alla terapia di prima linea.
    - PD come migliore risposta dopo almeno 4 cicli completi di R-CHOP (rituximab, ciclofosfamide, idrossidaunorubicina, oncovin e prednisone) come terapia di prima linea;
    - malattia stabile (SD) dopo 6 cicli R-CHOP come terapia di prima linea;
    - PR come migliore risposta dopo almeno 6 cicli R-CHOP e progressione della malattia dimostrata con biopsia (salvo se proibito a causa delle comorbilità) entro =12 mesi dal completamento della terapia di prima linea;
    - malattia recidivante definita come remissione completa a una terapia di prima linea seguita da progressione della malattia dimostrata con biopsia (salvo se proibito a causa delle comorbilità) entro =12 mesi dal completamento della terapia di prima linea.
    3. I partecipanti devono aver ricevuto una terapia di prima linea adeguata contenente almeno la combinazione di un regime a base di antraciclina e rituximab (anticorpo monoclonale anti-CD20). Le terapie locali (es. radioterapia) non saranno considerate come linea di terapia se eseguite durante la stessa linea di trattamento.
    4. Il tessuto tumorale archiviato incluso in paraffina acquisito =3 anni prima dello screening per la verifica patologica centrale per confermare la diagnosi di DLBCL e per l’analisi dell’espressione CD20/CD19 deve essere messo a disposizione per la partecipazione a questo studio. Se il tessuto tumorale archiviato incluso in paraffina non è disponibile, deve essere messo a disposizione per questo protocollo un campione di tessuto tumorale fresco (preferibile) oppure una biopsia con ago.
    5. Partecipanti ritenuti non idonei a ricevere HDC seguita da ASCT in base alla valutazione del medico curante e che soddisfano i seguenti criteri:
    • Età =18 anni e
    - precedente ASCT (come consolidamento di prima linea), o
    - indice di comorbilità specifico per il trapianto di cellule ematopoietiche (HCT- CI) >3.
    • Età =65 anni e 1 dei seguenti criteri:
    - precedente ASCT (come consolidamento di prima linea), o
    - comorbilità valutate da un punteggio HCT-CI >3, o
    - compromissione della funzione cardiaca (frazione di eiezione ventricolare sinistra (LVEF) <50%), o
    - compromissione della funzione renale (clearance della creatinina [CrCL] <60 ml/min stimata secondo la formula MDRD
    (Modification of Diet in Renal Disease), o
    - compromissione della funzione polmonare (capacità di diffusione per monossido di carbonio o volume espiratorio forzato in 1 secondo del 66%-80%) oppure dispnea su attività leggera, o
    - performance status ECOG (Eastern Cooperative Oncology Group) >1. Nelle cartelle originali del paziente deve essere documentata la motivazione di non idoneità per ASCT.
    Inoltre, tutti i partecipanti devono soddisfare i seguenti criteri:
    6. Età =18 anni.
    7. Malattia misurabile secondo i criteri di Lugano. La lesione deve essere positiva su tomografia a emissione di positroni.
    8. Aspettativa di vita stimata >3 mesi per altri motivi diversi dalla malattia primaria.
    9. Le donne in età fertile devono acconsentire a utilizzare metodi contraccettivi altamente efficaci
    PER UN ELENCO COMPLETO DEI CRITERI DI INCLUSIONE, FARE RIFERIMENTO AL PROTOCOLLO DELLO STUDIO
    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. Controindicazioni per R-GemOx e BR più polatuzumab vedotin secondo il giudizio del medico curante.
    2. Precedente terapia con recettore chimerico per l’antigene o altra terapia con linfociti T geneticamente modificati.
    3. Performance status ECOG >2.
    4. Conta assoluta dei neutrofili <1000/µl (salvo secondaria all’interessamento del midollo osseo da parte del DLBCL come dimostrato dalla biopsia di midollo osseo richiesta per lo screening).
    5. Conta piastrinica <50000/µl (salvo secondaria all’interessamento del midollo osseo da parte del DLBCL come dimostrato dalla biopsia di midollo osseo richiesta per lo screening).
    6. Conta assoluta dei linfociti <100/µl.
    7. Partecipanti con anamnesi attuale o pregressa di interessamento SNC del linfoma.
    8. Anamnesi nota di infezione da virus dell’immunodeficienza umana o infezione attiva da virus dell’epatite B (positività all’antigene di superficie dell’epatite B).
    9. Anamnesi nota di infezione da virus dell’epatite C, salvo se trattata e negativa al test effettuato mediante reazione a catena della polimerasi.
    10. Infezione attiva con SARS-CoV-2.
    11. Anamnesi nota o evidenza di stato gravemente immunocompromesso, ovvero trattamento corticosteroideo >10 mg/giorno per oltre 6 mesi.
    12. Hanno ricevuto vaccinazione con vaccini vivi entro 6 settimane prima della randomizzazione.
    13. Precedente terapia mirata a CD19.
    14. Anamnesi nota o presenza di attività convulsive o assunzione di farmaci anticonvulsivi attivi entro i 12 mesi antecedenti.
    15. Presenza di malattia del SNC che, secondo il giudizio dello sperimentatore, potrebbe inficiare la capacità di valutare la neurotossicità.
    16. Anamnesi nota o presenza di malattia autoimmune del SNC, come sclerosi multipla, neurite ottica o altra malattia infiammatoria o immunologica.
    17. Anamnesi nota o presenza di incidente cerebro-vascolare (CVA) entro 12 mesi prima della randomizzazione. Nota: in caso di anamnesi di CVA >12 mesi prima della leucaferesi, il partecipante non deve avere deficit neurologici instabili o potenzialmente fatali.
    18. Partecipanti con trasformazione di Richter o sindrome di Richter.
    19. Partecipanti che stanno assumendo qualsiasi altro trattamento sperimentale o durante le precedenti 4 settimane o 5 emivite.
    20. Insufficienza cardiaca clinica con classe della New York Heart Association =2 o LVEF <30%.
    21. Saturazione di ossigeno periferica a riposo <90% in aria ambiente.
    22. Disfunzione epatica indicata da bilirubina totale, aspartato aminotransferasi e/o alanina aminotransferasi >5 volte il limite superiore del valore normale (ULN) istituzionale.
    23. Creatinina sierica =2,0 × ULN o CrCl <30 ml/min calcolata secondo la formula MDRD modificata.
    24. Donne in stato di gravidanza o che allattano.
    25. Anamnesi precedente di neoplasie maligne diverse da DLBCL, a meno che il partecipante sia stato libero da malattia per =3 anni prima dello screening. Le eccezioni al limite temporale di =3 anni comprendono i seguenti casi:
    • carcinoma basocellulare della cute;
    • carcinoma cutaneo a cellule squamose;
    • carcinoma in situ della cervice uterina;
    • carcinoma in situ della mammella;
    • carcinoma in situ della vescica;
    • rilevazione istologica incidentale di cancro della prostata localizzato non trattato (T1a o T1b) sotto sorveglianza.
    26. Anamnesi di grave reazione da ipersensibilità immediata contro qualsiasi farmaco o relativi ingredienti/impurità di cui si prevede la somministrazione durante la partecipazione allo studio, es. all’interno del protocollo di linfodeplezione obbligatoria, premedicazione per l’infusione o farmaco/terapie di soccorso per le tossicità correlate al trattamento.
    27. Qualsiasi condizione clinica che potrebbe interferire con la valutazione della sicurezza o dell’efficacia del trattamento in studio.
    28. Rifiuto di partecipare al follow-up a lungo termine (LTFU) CAR T.
    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.
    Sopravvivenza libera da progressione (PFS), definita come il periodo di tempo tra la data della randomizzazione e la data della progressione della malattia obiettiva o del decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo, in base alla valutazione del Comitato di revisione indipendente (IRC).
    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.
    Il periodo di tempo tra la data della randomizzazione e la data della progressione della malattia obiettiva o del decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo, in base alla valutazione del Comitato di revisione indipendente (IRC).
    E.5.2Secondary end point(s)
    1. Event-free-survival (EFS; progression of disease, start of new anticancer 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-¿ and TNFa).
    • 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.
    Endpoint di efficacia primari:
    1. Sopravvivenza libera da eventi (EFS; progressione della malattia, inizio di un nuovo trattamento antitumorale, recidiva o decesso per qualsiasi causa), definita come il periodo di tempo tra la data della randomizzazione e la data dell’evento.
    2. Migliore tasso di risposta completa (BCRR), definito come la proporzione di partecipanti con almeno una valutazione della risposta completa, sulla base della valutazione dell’IRC.
    3. Durata della risposta completa, definita come il tempo di tempo che intercorre tra la data di una prima risposta completa (CR) e la data della valutazione della recidiva o la data del decesso a causa del DLBCL, a seconda di quale evento si verifichi per primo, sulla base della valutazione dell’IRC.
    4. Sopravvivenza globale (OS), definita come il periodo di tempo tra la data della randomizzazione e la data del decesso per qualsiasi causa.
    Altri endpoint secondari:
    • tassi PFS a 6 e 12 mesi, sulla base della valutazione dello sperimentatore e/o dell’IRC;
    • BCRR, definito come la proporzione di partecipanti con almeno una valutazione CR, sulla base della valutazione dello sperimentatore;
    • durata della risposta completa, definita come il periodo di tempo che intercorre tra la data di una prima CR e la data della valutazione della recidiva o la data del decesso a causa del DLBCL, a seconda di quale evento si verifichi per primo, sulla base della valutazione dello sperimentatore;
    • durata della risposta (DOR), definita come il periodo di tempo che intercorre tra la data di una prima risposta obiettiva (CR/risposta parziale [PR]) e la data della valutazione della recidiva o la data del decesso a causa del DLBCL, a seconda di quale evento si verifichi per primo, sulla base della valutazione dello sperimentatore e/o dell’IRC;
    • tempo alla risposta obiettiva (TTR), definito come il periodo di tempo che intercorre tra la data della randomizzazione e la data di una prima risposta obiettiva (CR/PR), sulla base della valutazione dello sperimentatore e/o dell’IRC;
    • tasso di risposta obiettiva (ORR), definito come la proporzione di partecipanti con una CR o una PR, sulla base della valutazione dello sperimentatore e/o dell’IRC;
    • tasso di risposta completa (CRR), definito come la proporzione di partecipanti con una CR, sulla base della valutazione dello sperimentatore e/o dell’IRC;
    • migliore risposta obiettiva (BOR), definita come la migliore risposta obiettiva nel momento tra la data della randomizzazione e la data dell’insorgenza della malattia progressiva (PD) o della recidiva, l’inizio di una nuova terapia antitumorale o la data del decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo, sulla base della valutazione dello sperimentatore e/o dell’IRC;
    • cambiamento dei sintomi B dal basale (febbre [>38 °C], sudorazione notturna e/o perdita di peso non intenzionale [=10% del peso corporeo]);
    • cambiamenti nell’HRQoL e nei sintomi del linfoma.
    Solo nel braccio MB-CART2019.1:
    • persistenza e fenotipo di MB-CART2019.1 e composizione delle cellule immunitarie, in base alle analisi di citometria a flusso e qPCR;
    • tipi e livelli di citochine (inclusi sIL-2R, IL-6, IL-10, IL-15,
    IFN-¿ e TNFa);
    • anticorpo anti-MB-CART2019.1.
    Endpoint di sicurezza:
    • tipo, frequenza e gravità degli eventi avversi (AE), eventi avversi gravi (SAE) ed eventi avversi di interesse speciale (AESI);
    • giorni di ricovero entro 7 mesi dopo la randomizzazione;
    • giorni di ricovero in terapia intensiva entro 7 mesi dopo la randomizzazione;
    • utilizzo di tocilizumab e/o steroidi ad alta dose;
    • necessità di trasfusioni, terapia antimicrobica profilattica e sostituzione delle gammaglobuline.
    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. Il periodo di tempo tra la data di randomizzazione e la data dell’evento.
    2. La proporzione di partecipanti con almeno una valutazione della risposta completa, sulla base della valutazione dell’IRC.
    3. Il periodo di tempo che intercorre tra la data di una prima risposta completa (CR) e la data della valutazione della recidiva o la data del decesso a causa del DLBCL, a seconda di quale evento si verifichi per primo, sulla base della valutazione dell’IRC.
    4. Il periodo di tempo tra la data di randomizzazione e la data del decesso per qualsiasi causa.
    PER UN ELENCO COMPLETO DEGLI INTERVALLI DI VALUTAZIONE, FARE RIFERIMENTO AL PROTOCOLLO DELLO STUDIO
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA39
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    France
    Germany
    Lithuania
    Netherlands
    Spain
    Sweden
    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 Ultimo Paziente
    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 days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    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: 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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 168
    F.4.2.2In the whole clinical trial 169
    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.
    Fino a 2 anni dopo la somministrazione, saranno eseguite regolari visite di follow-up a lungo termine. Il medico curante valuta le opzioni post-trattamento del singolo paziente; es. possibilità di partecipare a ulteriori studi sperimentali e/o trattamento secondo prescrizione personale. Dopo il completamento del follow-up a lungo termine, i pazienti proseguiranno in una sperimentazione di follow-up successiva per altri 13 anni.
    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 Decision2021-10-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-21
    P. End of Trial
    P.End of Trial StatusOngoing
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