KYV-101 for Rheumatoid arthritis

Inclusion criteria

• {"criterion_text":"- Understand and voluntarily sign an informed consent form\n- Male subjects unless surgically sterile, must agree to use two accepta-ble methods for contraception (e.g. spermicide and condom) during the trial and refrain from fathering a child starting from the time of signing the Informed Consent Form (ICF) until 12 months after dosing of the IMP or rituximab\n- Females of childbearing potential (FCBP) must have a negative seum pregnancy test at screening and must agree to use a highly effective contraceptive method (Pearl index <1) starting from the time of signing the ICF and for 12 months after dosing of the IMP or rituximab\n- Updated vaccination record according to the STIKO recommendations for immunocompromised patients\n- Male or female, age ≥ 18 and ≤ 80 years at time of consent\n- Able to adhere to the study visits and protocol\n- Fulfilment of the 2010 ACR-EULAR RA classification criteria\n- ACPA positivity (cut off 20 mU/ml) at Screening\n- Disease Activity Score DAS28-ESR>3.2 at Screening\n- Failure (defined as inadequate response after at least 3 months of therapy) of at least one conventional DMARD and at least two tsDMARD/bDMARDs\n- At least one swollen joint with Power Doppler activity of at least grade 1 or B-mode activity of at least grade 2 at Screening\n- Willingness to participate in a synovial puncture and biopsy"}

Exclusion criteria

• {"criterion_text":"- ANC < 1.000/mm3, ALC < 500/mm3 or hemoglobin < 8g/dl, absolute CD3+T cell count < 100/µl\n- Females who are intending to conceive during the study\n- Known hypersensitivity to any drug components\n- Malignancy in the last 5 years before screening (except basal or squamous cell skin cancer)\n- Requirement for immunization with live vaccine during the study period or within 14 days preceding leukapheresis\n- Subjects who are younger than 18 years or are incapable to understand the aim, importance and consequences of the study and to give legal informed consent (according to § 40 Abs. 4 and § 41 Abs. 2 and Abs. 3 AMG)\n- Have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the Investigator, may increase the risks associated with study participation or study agent administration, or may interfere with interpretation of results,\n- Subjects who possibly are dependent on the Sponsor, the Principal Investigator or Investigator (e.g. family members).\n- Subjects who are institutionalized by order of court or public authority\n- Subjects participating in another clinical trial with an investigational medicinal product or medical device (3 months before this trial)\n- Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh B or C), heart and pulmonary (NYHA IIIIV, blood oxygenation <92%) function\n- Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study\n- Prior treatment with anti-CD19 antibody therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR T cell therapy)\n- Only in phase II: Prior treatment of rituximab < 7 months before baseline OR ≥ 7 months before baseline) and B cell level < 0.1/nl\n- History of bone marrow/ hematopoietic stem cell or solid organ transplantation\n- csDMARD other than MTX at baseline\n- Any concomitant severe active infection, e.g. HIV, hepatitis B or C, SARS-CoV-2 (COVID-19), or active tuberculosis as defined by a positive Quantiferon TB-test. If presence of latent tuberculosis is estab-lished then treatment according to local guidelines must have been initiated prior to enrollment\n- Pregnant or lactating females"}

Primary endpoints

• {"endpoint_text":"- Safety (Phase I): Incidence and grading of severity (graded 0-4) of Cytokine Release Syndrome (CRS) and of Immune cCell Associated Neurotoxicity Syndrome (ICANS) as well as AE and SAE due to IMP within the first 4 weeks after anti-CD19 CAR T cell therapy. Participants of Phase I will continue to be observed over a total period of 52 weeks for AE and SAE, ACPA seroconversion and efficacy endpoints.","definition_or_measurement_approach":"Incidence and grading of CRS and ICANS graded 0-4; monitoring of AE and SAE within first 4 weeks; continued observation for AE/SAE, ACPA seroconversion and efficacy up to 52 weeks."}
• {"endpoint_text":"- Safety (Phase II): AE and SAE due to IMP and rituximab throughout the whole study.","definition_or_measurement_approach":"Recording and reporting of adverse events (AE) and serious adverse events (SAE) attributable to IMP or rituximab throughout study duration."}
• {"endpoint_text":"- Efficacy (Phase II): Percentage of subjects with ACPA seroconversion = ACPA level <20 mU/ml at week 16.","definition_or_measurement_approach":"ACPA seroconversion defined as ACPA level <20 mU/ml measured at week 16; endpoint = percentage of subjects meeting this criterion."}

Secondary endpoints

• {"endpoint_text":"- Clinical secondary endpoint (Phase II): Drug free survival time (beginning of immunosuppression for RA treatment except for stable dosage of MTX in the control arm) from week 7 to 52","definition_or_measurement_approach":"Time-to-event: drug-free survival measured from week 7 to week 52 (start of immunosuppression for RA treatment except stable MTX in control)."}
• {"endpoint_text":"- Clinical secondary endpoint (Phase II): Time to relapse/flare from week 7 to week 52","definition_or_measurement_approach":"Time-to-relapse/flare measured between week 7 and week 52."}
• {"endpoint_text":"- Clinical secondary endpoint (Phase II): ACR 20/50/70 response at week 16, 24 and 52 weeks","definition_or_measurement_approach":"ACR20/50/70 response rates assessed at weeks 16, 24 and 52."}
• {"endpoint_text":"- Clinical secondary endpoint (Phase II): DAS28-CRP remission at 16, 24, and 52 weeks","definition_or_measurement_approach":"DAS28-CRP remission status assessed at weeks 16, 24 and 52."}
• {"endpoint_text":"- Clinical secondary endpoint (Phase II): DAS28-CRP<3.2 at week 16, 24 and 52","definition_or_measurement_approach":"Proportion with DAS28-CRP <3.2 measured at weeks 16, 24 and 52."}
• {"endpoint_text":"- Clinical secondary endpoint (Phase II): SDAI remission at 16, 24, and 52 weeks","definition_or_measurement_approach":"SDAI remission assessed at weeks 16, 24 and 52."}
• {"endpoint_text":"- Clinical secondary endpoint (Phase II): Boolean 2.0 remission at 16, 24, and 52 weeks","definition_or_measurement_approach":"Boolean 2.0 remission status assessed at weeks 16, 24 and 52."}
• {"endpoint_text":"- Clinical secondary endpoint (Phase II): Change in DAS28-CRP at 16, 24, and 52 weeks","definition_or_measurement_approach":"Change from baseline in DAS28-CRP measured at weeks 16, 24 and 52."}
• {"endpoint_text":"- Clinical secondary endpoint (Phase II): Change in ACR score components at 16, 24, and 52 weeks","definition_or_measurement_approach":"Change from baseline in ACR score components at weeks 16, 24 and 52."}
• {"endpoint_text":"- Clinical secondary endpoint (Phase II): Change in SDAI and CDAI at 16, 24, and 52 weeks","definition_or_measurement_approach":"Change from baseline in SDAI and CDAI at weeks 16, 24 and 52."}
• {"endpoint_text":"- Clinical secondary endpoint (Phase II): Number of flares until 16, 24 and 52 weeks","definition_or_measurement_approach":"Count of flares recorded up to weeks 16, 24 and 52."}
• {"endpoint_text":"- Cellular and humoral response (Phase II): Percentage of subjects with ACPA seroconversion = ACPA level <20 mU/ml at week 24 and 52","definition_or_measurement_approach":"ACPA seroconversion defined as ACPA <20 mU/ml measured at weeks 24 and 52; endpoint = percentage of subjects."}
• {"endpoint_text":"- Cellular and humoral response (Phase II): Duration of persistence of CAR T cells in the peripheral blood","definition_or_measurement_approach":"Measurement of persistence duration of CAR T cells in peripheral blood over time (assay details not specified)."}
• {"endpoint_text":"- Cellular and humoral response (Phase II): Duration of B cell depletion in the peripheral blood","definition_or_measurement_approach":"Duration of peripheral B cell depletion measured over time."}
• {"endpoint_text":"- Cellular and humoral response (Phase II): Expansion of CAR T cells in the patient over time","definition_or_measurement_approach":"Kinetics/expansion of CAR T cells in peripheral blood over time."}
• {"endpoint_text":"- Cellular and humoral response (Phase II): Change in ACPA levels (mU/ml) over time","definition_or_measurement_approach":"Serial measurement of ACPA levels (mU/ml) over study visits/timepoints."}
• {"endpoint_text":"- Cellular and humoral response (Phase II): Change in RF levels (U/ml) over time","definition_or_measurement_approach":"Serial measurement of RF levels (U/ml) over time."}
• {"endpoint_text":"- Cellular and humoral response (Phase II): Change in ACPA levels (mU/ml) in HLA-defined subgroups over time","definition_or_measurement_approach":"Subgroup analyses of ACPA level changes over time stratified by HLA-defined subgroups."}
• {"endpoint_text":"- Cellular and humoral response (Phase II): Change in levels of ACPA isotypes and IgG subclasses at week over time","definition_or_measurement_approach":"Measurement of ACPA isotypes and IgG subclass levels over time (timepoints not fully specified)."}
• {"endpoint_text":"- Cellular and humoral response (Phase II): Change in total IgG, IgG subclasses and IgA, IgM immunoglobulins over time","definition_or_measurement_approach":"Serial immunoglobulin measurements (total IgG, subclasses, IgA, IgM) over time."}
• {"endpoint_text":"- Cellular and humoral response (Phase II): Change in the number of plasmablasts, B cell and T cell numbers over time in peripheral blood","definition_or_measurement_approach":"Flow cytometry or cell counts of plasmablasts, B and T cells over time in peripheral blood."}
• {"endpoint_text":"- additional endpoint (Phase II): Patient’s Global Assessment (PtGA) of disease activity (VAS 0-100mm)","definition_or_measurement_approach":"PtGA measured by VAS 0-100 mm at specified visits."}
• {"endpoint_text":"- additional endpoint (Phase II): Physician’s Global Assessment (PhGA) of disease activity (VAS 0-100mm)","definition_or_measurement_approach":"PhGA measured by VAS 0-100 mm at specified visits."}
• {"endpoint_text":"- additional endpoint (Phase II): Health Assessment Questionnaire – Disease Index (HAQ-DI)","definition_or_measurement_approach":"HAQ-DI questionnaire scores over time."}
• {"endpoint_text":"- additional endpoint (Phase II): Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT)","definition_or_measurement_approach":"FACIT-Fatigue questionnaire scores over time."}
• {"endpoint_text":"- additional endpoint (Phase II): Short Form 36 (SF-36, quality of life questionnaire)","definition_or_measurement_approach":"SF-36 QoL scores collected per schedule."}
• {"endpoint_text":"- additional endpoint (Phase II): Questionnaire on work productivity and activity impairment (WPAI)","definition_or_measurement_approach":"WPAI questionnaire scores over time."}
• {"endpoint_text":"- additional endpoint (Phase II): Change in hand strength over time","definition_or_measurement_approach":"Objective measurement of hand strength at visits and change from baseline."}
• {"endpoint_text":"- additional endpoint (Phase II): Change in radiological Sharp-van-der-Heijde score (hands and feet)","definition_or_measurement_approach":"Radiographic Sharp-van-der-Heijde scoring of hands and feet and change from baseline."}
• {"endpoint_text":"- additional endpoint (Phase II): Change in MRI RAMRIS score","definition_or_measurement_approach":"MRI RAMRIS scoring changes over time."}
• {"endpoint_text":"- additional endpoint (Phase II): Change of EULAR-OMERACT US synovitis scoring system","definition_or_measurement_approach":"Ultrasound EULAR-OMERACT synovitis score change over time."}
• {"endpoint_text":"- Exploratory endpoint (Phase II): Change in ACPA specific plasmablasts and B cells","definition_or_measurement_approach":"Immunophenotyping of ACPA-specific plasmablasts and B cells over time."}
• {"endpoint_text":"- Exploratory endpoint (Phase II): To analyze the changes in B cell receptor repertoire","definition_or_measurement_approach":"B cell receptor repertoire sequencing and analysis over time."}
• {"endpoint_text":"- Exploratory endpoint (Phase II): To evaluate the therapy-induced changes of B cell subsets","definition_or_measurement_approach":"Flow cytometry characterization of B cell subset changes post-therapy."}
• {"endpoint_text":"- Exploratory endpoint (Phase II): Characterizing B Cell and Plasma Cell Niches in Tissues","definition_or_measurement_approach":"Tissue analyses (biopsy) to characterize B cell/plasma cell niches; methods not fully specified."}
• {"endpoint_text":"- Exploratory endpoint (Phase II): To evaluate the influence of therapy on auto-antigen-specific B cells","definition_or_measurement_approach":"Assessment of auto-antigen-specific B cells in peripheral blood and tissues over time."}
• {"endpoint_text":"- Exploratory endpoint (Phase II): To evaluate the therapy-induced alterations of T cell compartments","definition_or_measurement_approach":"Characterization of T cell compartment changes post-therapy."}
• {"endpoint_text":"- Exploratory endpoint (Phase II): To evaluate the impact of therapy on Immunoglobulin glycosylation","definition_or_measurement_approach":"Analysis of immunoglobulin glycosylation patterns pre- and post-therapy."}
• {"endpoint_text":"- Exploratory endpoint (Phase II): To evaluate changes in lymphocyte numbers and composition in bone marrow biopsy, synovial biopsy, lymph node biopsy and synovial fluid","definition_or_measurement_approach":"Cell counts and composition analyses from bone marrow, synovial, lymph node biopsies and synovial fluid."}
• {"endpoint_text":"- Exploratory endpoint (Phase II): To repeat all statistical assessments using pooled data from CAR T patients in phase I and II","definition_or_measurement_approach":"Pooled statistical analyses of CAR T patients across phase I and II cohorts."}

Other endpoints

• {"endpoint_text":"- additional endpoint (Phase II): Patient’s Global Assessment (PtGA) of disease activity (VAS 0-100mm)\n- additional endpoint (Phase II): Physician’s Global Assessment (PhGA) of disease activity (VAS 0-100mm)\n- additional endpoint (Phase II): Health Assessment Questionnaire – Disease Index (HAQ-DI)\n- additional endpoint (Phase II): Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT)\n- additional endpoint (Phase II): Short Form 36 (SF-36, quality of life questionnaire)\n- additional endpoint (Phase II): Questionnaire on work productivity and activity impairment (WPAI)\n- additional endpoint (Phase II): Change in hand strength over time\n- additional endpoint (Phase II): Change in radiological Sharp-van-der-Heijde score (hands and feet)\n- additional endpoint (Phase II): Change in MRI RAMRIS score\n- additional endpoint (Phase II): Change of EULAR-OMERACT US synovitis scoring system\n- Exploratory endpoint (Phase II): Change in ACPA specific plasmablasts and B cells\n- Exploratory endpoint (Phase II): To analyze the changes in B cell receptor repertoire\n- Exploratory endpoint (Phase II): To evaluate the therapy-induced changes of B cell subsets\n- Exploratory endpoint (Phase II): Characterizing B Cell and Plasma Cell Niches in Tissues\n- Exploratory endpoint (Phase II): To evaluate the influence of therapy on auto-antigen-specific B cells\n- Exploratory endpoint (Phase II): To evaluate the therapy-induced alterations of T cell compartments\n- Exploratory endpoint (Phase II): To evaluate the impact of therapy on Immunoglobulin glycosylation\n- Exploratory endpoint (Phase II): To evaluate changes in lymphocyte numbers and composition in bone marrow biopsy, synovial biopsy, lymph node biopsy and synovial fluid\n- Exploratory endpoint (Phase II): To repeat all statistical assessments using pooled data from CAR T patients in phase I and II","definition_or_measurement_approach":"See individual endpoint definitions above (quality-of-life instruments: PtGA, PhGA, HAQ-DI, FACIT, SF-36, WPAI; imaging scores: Sharp-van-der-Heijde, RAMRIS, EULAR-OMERACT; immunologic and cellular assessments as described)."}

Germany

Earliest CTIS Part Ii Submission Date

10-10-2024

Latest Decision Or Authorization Date

13-01-2026

Processing Time Days

460

Number Of Sites

1

Number Of Participants

16

Primary sponsor

Full Name

Charite Universitaetsmedizin Berlin KöR

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Germany

Contract research organisations

Name

ALGORA Gesellschaft fuer Medizinstatistik und Vertriebssysteme mbH

Responsibilities

codes: 1, 6

Third parties

• {"country":"Germany","full_name":"Universitaetsklinikum Erlangen AöR","duties_or_roles":"","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"German Rheumatism Research Centre","duties_or_roles":"sample storage","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"Radiologie am Kudamm (vendor for radiology assessments)","duties_or_roles":"radiology assessments","organisation_type":"Health care"}
• {"country":"United States","full_name":"Kyverna Therapeutics Inc.","duties_or_roles":"IMP production","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"ALGORA Gesellschaft fuer Medizinstatistik und Vertriebssysteme mbH","duties_or_roles":"","organisation_type":"Pharmaceutical company"}