A Phase I/IIa open label single ascending dose study to assess safety and tolerability of regulatory T cells to promote discontinuation of tacrolimus monotherapy in liver transplant recipients - LiveTreg
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 27
- 试验地点
- 1
- 主要终点
- 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
研究概览
简要总结
Determine that autologous polyclonal ex-vivo expanded Tregs (Treg02) therapy in liver transplant recipients who are already receiving tacrolimus monotherapy is safe, well tolerated and modulates the immunologic response in the patient to enable permanent withdrawal of immunosuppression
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 否
入选标准
- •Adult patients (≥18 years of age) with end-stage liver disease who have had single liver transplant
- •Willing and able to give signed and dated informed consent* for participation in the trial participate in the trial
- •Negative SARS-CoV-2 test (depending on current recommendations)
- •No evidence of marked abnormality in latest liver protocol biopsy around 1 year post LT or at inclusion
- •>24 months, < 60 months from the date of liver transplantation
- •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).
- •Inflammation grade < 4 and fibrosis stage < 3 in accordance with grading and staging recommendations
- •RAI < 3 at the last biopsy or at inclusion
- •At least 6 months stable on tacrolimus monotherapy with target trough levels of 5 ng/ml without complications
- •No evidence of hepatic autoimmune disease (primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis)
- •Haematology: Hb ≥ 7.0 g/dl; platelets ≥ 80x10^9/l; total leukocyte count: ≥ 3.0x10^9/l
- •In the investigator’s opinion, is able and willing to comply with all the trial requirements
排除标准
- •Patient has previously received any tissue or organ transplant other than single liver transplant
- •HCV-RNA serum positive, HIV positive, HBV surface antigen or HBV-DNA detected in serum at the day of inclusion into the trial
- •Ongoing treatment with systemic immunosuppressive drugs other than tacrolimus at study entry
- •Malignant or pre-malignant haematological conditions. Multiple myeloma, light or heavy chain deposition disease
- •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
- •Known allergy/hypersensitivity to any component of the study product
- •Known contraindication to the protocol-specified treatments / medications
- •Liver transplant dysfunction defined as fibrosis stage >3, Albumin <3 g/l and ALT >62 IU/l (>2 ULN)
- •Severe irreversible obstructive or restrictive lung disease
- •Previous treatment with any desensitization procedure with or without intravenous immunoglobulin
- •HCC patients with high risk of recurrence as defined >G1/2, >L0, >V0 and > unifocal as defined by Edmondson-Steiner HCC grading scheme
- •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)
- •Active or systemic immune disease that precludes discontinuation of immunosuppression
- •Evidence of significant local or systemic infection
研究组 & 干预措施
Histakut Dimetindenmaleat 1 mg/ml Injektionslösung, Paracetamol-ratiopharm® 500 mg Tabletten
干预措施: Histakut Dimetindenmaleat 1 mg/ml Injektionslösung (Drug)
Histakut Dimetindenmaleat 1 mg/ml Injektionslösung, Paracetamol-ratiopharm® 500 mg Tabletten
干预措施: Paracetamol-ratiopharm® 500 mg Tabletten (Drug)
Advagraf 1 mg prolonged-release hard capsules, Prograf 0,5 mg Hartkapseln, Envarsus 1 mg prolonged-release tablets
干预措施: Advagraf 1 mg prolonged-release hard capsules (Drug)
Advagraf 1 mg prolonged-release hard capsules, Prograf 0,5 mg Hartkapseln, Envarsus 1 mg prolonged-release tablets
干预措施: Prograf 0,5 mg Hartkapseln (Drug)
Advagraf 1 mg prolonged-release hard capsules, Prograf 0,5 mg Hartkapseln, Envarsus 1 mg prolonged-release tablets
干预措施: Envarsus 1 mg prolonged-release tablets (Drug)
Treg02
干预措施: Treg02 (Drug)
结局指标
主要结局
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
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
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
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
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.
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.
次要结局
- 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
- Secondary indices of efficacy 2: Incidence of patients treated for subclinical acute rejection based on histopathological findings
- 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
- Secondary indices of efficacy 4: Reduced incidence of adverse events/rejections following tapering of immunosuppression (e.g. cardiovascular complications, drug toxicity, etc.)
- 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.
- Assess health-related quality of life by the SF-12 questionnaire
研究者
Prof. Dr. med. Petra Reinke
Scientific
Charite Universitaetsmedizin Berlin KöR