Tacrolimus for Liver transplantation

Inclusion criteria

• {"criterion_text":"- Adult patients (≥18 years of age) with end-stage liver disease who have had single liver transplant\n- >24 months, < 60 months from the date of liver transplantation\n- Stable liver function as determined by clinical studies; direct bilirubin (< 17.1 µmol/l or 1 mg/dl, total bilirubin < 2.2 mg/dl, albumin > 3 g/l and ALT < 62 IU/l (< 2 ULN).\n- Inflammation grade < 4 and fibrosis stage < 3 in accordance with grading and staging recommendations\n- RAI < 3 at the last biopsy or at inclusion\n- At least 6 months stable on tacrolimus monotherapy with target trough levels of 5 ng/ml without complications\n- No evidence of hepatic autoimmune disease (primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis)\n- Haematology: Hb ≥ 7.0 g/dl; platelets ≥ 80x10^9/l; total leukocyte count: ≥ 3.0x10^9/l\n- In the investigator’s opinion, is able and willing to comply with all the trial requirements\n- Willing and able to give signed and dated informed consent* for participation in the trial participate in the trial\n- Negative SARS-CoV-2 test (depending on current recommendations)\n- No evidence of marked abnormality in latest liver protocol biopsy around 1 year post LT or at inclusion"}

Exclusion criteria

• {"criterion_text":"- Patient has previously received any tissue or organ transplant other than single liver transplant\n- Known contraindication to the protocol-specified treatments / medications\n- Liver transplant dysfunction defined as fibrosis stage >3, Albumin <3 g/l and ALT >62 IU/l (>2 ULN)\n- Severe irreversible obstructive or restrictive lung disease\n- Previous treatment with any desensitization procedure with or without intravenous immunoglobulin\n- HCC patients with high risk of recurrence as defined >G1/2, >L0, >V0 and > unifocal as defined by Edmondson-Steiner HCC grading scheme\n- Concomitant malignancy or history of malignancy prior to study inclusion in the trial (excluding successfully treated non-metastatic basal/squamous cell carcinoma of the skin, successfully embolized HCC)\n- Active or systemic immune disease that precludes discontinuation of immunosuppression\n- Evidence of significant local or systemic infection\n- HCV-RNA serum positive, HIV positive, HBV surface antigen or HBV-DNA detected in serum at the day of inclusion into the trial\n- Ongoing treatment with systemic immunosuppressive drugs other than tacrolimus at study entry\n- Malignant or pre-malignant haematological conditions. Multiple myeloma, light or heavy chain deposition disease\n- Participation in another clinical trial during the study or within 5 times as the half-life time of the drug used in the previous trial prior to planned study entry\n- Known allergy/hypersensitivity to any component of the study product"}

Primary endpoints

• {"endpoint_text":"- Primary safety endpoint 1: Acute toxicity associated with infusion of Treg02 will be assessed by evidence of: (a) pulmonary complications, (b) immunological reactions resulting in anaphylactic reactions, immediate cardiovascular compromise, or other acute organ failure, (c) Treg therapy associated biochemical perturbation (significant deviations in biomarker data) as assessed by the immunological impact of the infused cells or apoptosis of Tregs and release of cellular contents","definition_or_measurement_approach":"Assessed by evidence of: (a) pulmonary complications, (b) immunological reactions (anaphylaxis, immediate cardiovascular compromise, other acute organ failure), (c) biochemical perturbations in biomarker data indicating immunological impact or apoptosis/release of cellular contents."}
• {"endpoint_text":"- Primary safety endpoint 2: Over-suppression of the immune system by assessing evidence of: (a) major and/or opportunistic infections, especially increased frequency of CMV, EBV and HBV, HCV reactivation and/or disease, (b) (early) development of neoplasia, (c) relevant anomalies in laboratory analysis unrelated to the transplanted liver functions","definition_or_measurement_approach":"Assessment of occurrences of major/opportunistic infections (including CMV, EBV, HBV, HCV reactivation), detection of new neoplasia, and laboratory anomalies not related to transplanted liver function."}
• {"endpoint_text":"- Primary clinical endpoint: Incidence of acute and/or chronic rejection and the prevalence of AEs. The principal measure of immunomodulation is biopsy-proven acute rejection (BPAR) within 14 months following Treg transfer. Histopathological grading of biopsy material will be assessed by the established Banff criteria.","definition_or_measurement_approach":"Principal measure: biopsy-proven acute rejection (BPAR) within 14 months after Treg transfer; histopathology graded using Banff criteria. Also incidence of chronic rejection and prevalence of adverse events."}

Secondary endpoints

• {"endpoint_text":"- Secondary indices of efficacy 1: Prevention of acute rejection: (a) Time to acute rejection episode, (b) Severity of acute rejection episodes based on response to treatment and histological scoring, (c) The level of total immunosuppression at the final trial visit","definition_or_measurement_approach":"Measured as time to first acute rejection, severity by treatment response and histological scoring."}
• {"endpoint_text":"- Secondary indices of efficacy 2: Incidence of patients treated for subclinical acute rejection based on histopathological findings","definition_or_measurement_approach":"Incidence measured by histopathological diagnosis leading to treatment for subclinical acute rejection."}
• {"endpoint_text":"- Secondary indices of efficacy 3: Prevention of chronic graft dysfunction (chronic rejection) will be assessed by clinically impaired levels of liver enzymes) and histopathological (Banff staging) criteria measures","definition_or_measurement_approach":"Assessment by clinically impaired liver enzyme levels and Banff histopathological staging."}
• {"endpoint_text":"- Secondary indices of efficacy 4: Reduced incidence of adverse events/rejections following tapering of immunosuppression (e.g. cardiovascular complications, drug toxicity, etc.)","definition_or_measurement_approach":"Incidence comparison of AEs and rejection events after tapering immunosuppression."}
• {"endpoint_text":"- Biomarker panel: Measure functional and molecular indices reflecting the immune response as well as treatment safety and efficacy of Tregs by a validated set of biomarkers; as detailed in the Clinical trial protocol.","definition_or_measurement_approach":"Measurement by a validated set of functional and molecular biomarkers as specified in the clinical trial protocol."}
• {"endpoint_text":"- Assess health-related quality of life by the SF-12 questionnaire","definition_or_measurement_approach":"Health-related quality of life measured using the SF-12 questionnaire."}

Germany

Earliest CTIS Part Ii Submission Date

10-12-2024

Latest Decision Or Authorization Date

06-02-2025

Processing Time Days

58

Number Of Sites

1

Number Of Participants

27

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

SCIRENT Clinical Research and Science GmbH

Responsibilities

Monitoring and Pharmacovigilance

Third parties

• {"country":"Germany","full_name":"CheckImmune GmbH","duties_or_roles":"Immunmonitoring/ Biomarker panel analyses","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"SCIRENT Clinical Research and Science GmbH","duties_or_roles":"Monitoring and Pharmacovigilance","organisation_type":"Pharmaceutical company"}