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    Summary
    EudraCT Number:2022-001796-14
    Sponsor's Protocol Code Number:CYTB323G12101
    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:2022-10-28
    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 number2022-001796-14
    A.3Full title of the trial
    An open-label, multi-center, phase 1/2 study to assess safety, efficacy and cellular kinetics of YTB323 in participants with severe, refractory autoimmune disorders.
    Estudio de fase I/II, abierto y multicéntrico en el que se evalúan la seguridad, la eficacia y la cinética celular de YTB323 en participantes con trastornos autoinmunes refractarios graves.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An open-label study to assess safety, efficacy and cellular kinetics of YTB323 in severe, refractory autoimmune disorders.
    Estudio abierto en el que se evalúan la seguridad, la eficacia y la cinética celular de YTB323 en trastornos autoinmunes refractarios graves.
    A.4.1Sponsor's protocol code numberCYTB323G12101
    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 SponsorNovartis Farmacéutica, S.A.
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica, S.A.
    B.5.2Functional name of contact pointTrial Monitoring Operations (TMO)
    B.5.3 Address:
    B.5.3.1Street AddressGran Vía de les Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number34 90 0353036
    B.5.5Fax number34 93 2479903
    B.5.6E-maileecc.novartis@novartis.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.3.2Product code YTB323
    D.3.4Pharmaceutical form Dispersion 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 INNNot estabilished
    D.3.9.3Other descriptive nameYTB323
    D.3.9.4EV Substance CodeSUB221189
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number5000000
    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.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
    Systemic Lupus Erythematosus
    Lupus Nephritis
    Lupus eritematoso sistémico
    Nefritis en el lupus
    E.1.1.1Medical condition in easily understood language
    Systemic Lupus Erythematosus
    Lupus Nephritis
    Lupus eritematoso sistémico
    Nefritis en el lupus
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10042945
    E.1.2Term Systemic lupus erythematosus
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess safety of YTB323 in participants with srSLE and other severe forms of autoimmune diseases
    Evaluar la seguridad de YTB323 en participantes con LESrg y otras formas graves de enfermedades autoinmunes.
    E.2.2Secondary objectives of the trial
    •To characterize the in vivo cellular kinetics (pharmacokinetics, PK) of YTB323 in peripheral blood by quantitative polymerase chain reaction (qPCR)
    •To characterize the incidence and prevalence of pre-existing and treatment induced immunogenicity (cellular and humoral) of YTB323
    •To evaluate feasibility of the manufacturing process in autoimmune disorders
    •Part A: To assess the effect of YTB323 on the following SLE disease activity scores
    •Part A: To evaluate effect of YTB323 for srSLE participants who also have active lupus nephritis
    -Caracterizar la cinética celular in vivo (farmacocinética [PK]) de YTB323 en sangre periférica mediante una prueba PCR (reacción en cadena de la polimerasa) cuantitativa.
    -Caracterizar la incidencia y prevalencia de la inmunogenicidad preexistente e inducida por el tratamiento (celular y humoral) de YTB323.
    -Evaluar la viabilidad del proceso de fabricación en los trastornos autoinmunes.
    -Parte A: evaluar el efecto de YTB323 en las siguientes puntuaciones de la actividad del LES.
    -Parte A: evaluar el efecto de YTB323 en participantes con LESrg que también presentan nefritis lúpica activa.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed informed consent.
    - Adequate renal, hepatic, cardiac, hematological and pulmonary function.
    - Men and women with SLE, aged ≥18 years and ≤65 years at acreening, fulfilling the 2019 European League Against Rheumatism EULAR/ACR classification criteria for SLE.
    - Patient must be positive for at least one of the following autoantibodies at screening: antinuclear antibodies (ANA) at a titer of ≥1:80, or anti dsDNA (above the ULN); or anti-Sm (above the ULN).
    - Active (severe) disease as defined by SLEDAI-2K ≥8 (not including the SLEDAI-2K domains of lupus headache, cerebrovascular accident, organic brain syndrome*) and at least one of the following significant SLE related organ involvements:
    - Renal
    - Peri/myocarditis
    - Pleuritis or other lung involvement
    - Other types of serositis such as peritoneal
    - Vasculitis

    - Failure to respond (i.e. having high disease activitiy as defined in criterion above despite the following therapy) to two or more standard immunosuppressive therapies (including one of mycophenolate or cyclophosphamide), unless contraindicated or having experienced documented adverse events or intolerance related to such immunosuppresive drugs not allowing their further use, in combination with glucocorticoids and failure to respond to at least on biological agent (unless contraindicated, the patient deemed ineligible by the Investigator or not available in a country).
    -Consentimiento informado firmado.
    -Funciones renal, hepática, cardíaca, hematológica y pulmonar adecuadas.
    -Pacientes de ambos sexos entre >/=18 años y </=65 años de edad en la selección que cumplan los criterios de clasificación del European League Against Rheumatism (EULAR) 2019/American College of Rheumatology (ACR) del LES.
    -Pacientes que hayan dado positivo en al menos uno de los siguientes autoanticuerpos en la selección: anticuerpos antinucleares (AAN) con un título >/=1:80 o anti-ADNbc (por encima del LSN); anti Sm (por encima del LSN).
    -Enfermedad (grave) activa definida por SLEDAI-2K >/=8 (que no incluye los dominios del SLEDAI-2K de cefalea por lupus, accidente cerebrovascular o síndrome cerebral orgánico*) y al menos una de las siguientes afectaciones orgánicas significativas relacionadas con el LES:
    --Renal
    --Pericarditis/miocarditis.
    --Pleuritis u otra afectación pulmonar.
    --Otros tipos de serositis, como la peritoneal.
    --Vasculitis.
    -Falta de respuesta (es decir, tener alta actividad de la enfermedad como se define en el criterio anterior, a pesar de la siguiente terapia) a dos o más tratamientos inmunosupresores de referencia (como uno de micofenolato o ciclofosfamida), salvo que esté contraindicado o que haya presentado acontecimientos adversos o intolerancia documentados en relación con esos fármacos inmunosupresores que no permitan seguir tomándolos, en combinación con glucocorticoides; y falta de respuesta a al menos un fármaco biológico (salvo que esté contraindicado, el investigador no considere elegible al paciente o que no esté disponible en un país).
    E.4Principal exclusion criteria
    - Clinically signficant active, opportunistic, chronic or recurrent infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, such as COVID-19 etc.) one month prior to or during screening.
    - Uncontrolled diabetes mellitus, lung diseases or any other illness that are not related to SLE that in the opinion of the Investigator would jeopardize the ability of the patient to tolerate lymphodepletion and CD19 CAR T cell therapy.
    - Prior history of malignancy except for localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured by local surgica therapy, such as head and neck cancer, or stage I breast cancer will be considered on an individual basis.
    - Any patients requiring medications probited by the protocol.
    - Any psychiatric condition or disability compliance with treatment or informed consent impossible.
    - Prior treatment with anti-CD19 therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR-T cell therapy).
    - History o bone marrow/hematopoietic stem cell or solid organ transplantation.
    - Female participants who are pregnant or breastfeeding or intending to conceive during the course of the study.
    - Women of childbearing potential, defined as all womoen physiologically capable of becoming pregnant, unless they are using a highly effective method of contraception starting from the time of enrollment to at least 12 months after the YTB323 infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests.
    - Sexually active males unwilling to use a condom during intercourse from the time enrollment for at least 12 months after YTB323 infusion and until CAR-T cells ar eno longer present by qPCR on two consecutive tests.
    - Any acute, severe lupus related flare during screening that needs immediate treatment and/or makes the immunosuppressive washout impossible; thus, makes the patient ineligibile for CD19 CAR-T therapy as judged by the Investigator, such as acute central nervous system (CNS) lupus (e.g. psychosis, epilespy) or catastrophic antiphospholipid syndrome.
    - Significant, likely irreversible organ damage related to SLE, e.g. end stage renal disease, where, in the opinion of the Investigator CD19 CAR-T cell therapy would be unlikely to benefit the patient.
    -Infección oportunista, activa, crónica o recurrente de interés clínico confirmada por evidencia clínica, diagnóstico por imagen o pruebas analíticas positivas (p. ej., cultivos de sangre, PCR de ADN/ARN, como COVID-19, etc.) un mes antes o durante la selección.
    -Diabetes mellitus no controlada, enfermedades pulmonares u otra enfermedad no relacionada con el LES que, en opinión del investigador, impediría que el paciente tolerara la linfodepleción y la terapia con linfocitos CAR-T dirigidos contra CD19.
    -Antecedentes de tumor maligno, salvo el carcinoma localizado de células basales o escamosas de la piel. Otros tumores malignos que se considere que puedan curarse con terapia quirúrgica local, como el cáncer de cabeza y cuello o el cáncer de mama en estadio 1, considerados de forma individual.
    -Cualquier paciente que requiera medicación prohibida por el protocolo.
    -Cualquier enfermedad o discapacidad psiquiátrica que imposibilite el cumplimiento del tratamiento o del consentimiento informado.
    -Tratamiento previo con anti-CD19, tratamiento adoptivo con linfocitos T o cualquier producto de terapia génica anterior (p. ej., terapia con linfocitos CAR-T).
    -Antecedentes de trasplante de médula ósea/células madre hematopoyéticas o de órganos sólidos.
    -Participantes que estén embarazadas o en periodo de lactancia o que piensen concebir durante el transcurso del estudio.
    -Las mujeres con posibilidad de quedarse embarazadas, definidas como todas las mujeres fisiológicamente capaces de quedarse embarazadas, salvo que accedan a utilizar un método anticonceptivo altamente eficaz desde el momento de su reclutamiento hasta al menos 12 meses después de la perfusión de YTB323 y hasta que no se observen linfocitos CAR-T mediante prueba PCR cuantitativa en dos pruebas consecutivas.
    -Los varones sexualmente activos que no deseen utilizar un preservativo durante el coito desde el momento de su reclutamiento hasta al menos 12 meses después de la perfusión de YTB323 y hasta que no se observen linfocitos CAR-T mediante prueba PCR cuantitativa en dos pruebas consecutivas.
    -Cualquier brote lúpico agudo grave durante la selección que precise tratamiento inmediato o imposibilite el lavado inmunosupresor; de este modo, el paciente no será elegible para una terapia con linfocitos CAR-T dirigidos contra CD19 según el criterio del investigador, como en el caso del lupus agudo del sistema nervioso central (SNC) (p. ej., psicosis o epilepsia) o del síndrome antifosfolípido catastrófico.
    -Daño significativo y probablemente irreversible en un órgano relacionado con el LES, p. ej., enfermedad renal en estadio terminal por el que, según la opinión del investigador, fuera improbable que la terapia con linfocitos CAR-T dirigidos contra CD19 beneficiara al paciente
    E.5 End points
    E.5.1Primary end point(s)
    •Number of participants with AEs and SAEs
    -Número de participantes con acontecimientos adversos y acontecimientos adversos graves
    E.5.1.1Timepoint(s) of evaluation of this end point
    720 days
    720 dias
    E.5.2Secondary end point(s)
    •CAR transgene levels by quantitative polymerase chain reaction (qPCR) in blood.
    •Cellular and humoral responses to CAR transgene.
    •Number of patients infused with planned target dose.
    •SLEDAI-2K
    •BILAG-2004
    •Physician's global assessment
    •LLDAS
    •Remission (DORIS)
    •SRI-4
    •BICLA
    •MCR
    •Urinary protein creatinine ratio
    •Complete Renal Response
    -Niveles del transgén CAR por reacción en cadena de la polimerasa cuantitativa (qPCR) en sangre.
    -Respuestas celulares y humorales al transgén CAR.
    -Número de pacientes infundidos con el tratamiento del ensayo con la dosis planeada
    -SLEDAI-2K.
    -BILAG-2004
    -PGA
    LLDAS
    -Remisión (DORIS)
    -SRI-4
    -BICLA
    -MCR
    -Proporción de proteína creatinina en orina
    -Respuesta renal completa
    E.5.2.1Timepoint(s) of evaluation of this end point
    720 days
    720 dias
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    New indication/patient population
    Nueva indicación/ población de pacientes
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    United States
    France
    Spain
    Germany
    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
    The end of study (or last participant last visit - LPLV) is when all participants have completed at least Month 24 evaluation or were withdrawn prematurely.
    El final del estudio (o última visita del último participante - LPLV) es cuando todos los participantes han completado al menos la evaluación del Mes 24 o se retiraron prematuramente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days9
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    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: 12
    F.1.3Elderly (>=65 years) No
    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 state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 8
    F.4.2.2In the whole clinical trial 12
    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)
    All participants who either complete or prematurely discontinue from the study will be asked to participate in a long term follow-up (LTFU, see Section 4.1 of Protocol) either within this study or a dedicated LTFU study. In the LTFU semiannual and/or annual evaluations will be performed up to 15 years from the date of infusion as recommended by health authority guidance for participants treated with gene therapies.
    A los participantes que completen o finalicen prematuramente se les pedirá que participen en un seguimiento a largo plazo (LTFU,Sección 4.1 del Protocolo) ya sea dentro de este estudio o en otro de seguimiento de largo plazo (LTFU). En el LTFU se realizarán evaluaciones semestrales y/o anuales hasta 15 años a partir de la fecha de la infusión del tratamiento del ensayo según lo recomendado por las guías de las autoridades sanitarias para los participantes que son tratados con terapias génicas
    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 Decision2023-02-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-02-06
    P. End of Trial
    P.End of Trial StatusOngoing
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