A Phase I/IIa open label single ascending dose study to investigate the safety and tolerability of regulatory T cells as an adjunctive therapy in deceased-donor kidney recipients - ProTreg
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, 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 whether administering polyclonal ex-vivo expanded autologous Tregs to deceased donor kidney transplant recipients is safe. Investigate if adoptive Treg therapy modulates the immunological response such that the kidney transplant is tolerated and safe. Yield preliminary data that Treg therapy could potentially enable maintenance immunosuppressive therapy tapering or elimination, thereby improving recipients’ long-term prognosis.
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
- •Chronic renal insufficiency with a GFR < 15 ml/min x 1.73 m², accepted by the organ transplantation conference, registered by ET (Eurotransplant; www.eurotransplant.org)
- •Age: 18 – 70 years of age
- •Willing and able to participate in the trial
- •Signed and dated written informed consent.* (*For patients unable to read and/or write, an oral informed consent observed by an independent witness is acceptable, if the patient has fully understood the oral information given by the Investigator. The witness should sign the consent form on behalf of the patient.)
- •Haematology: Hb ≥7.0 g/dl; platelets ≥80x10^9/l; total leukocyte count: ≥3.0x10^9/l
- •Karnofsky score: 40 – 90
- •Donor eligibility criteria: Individuals 18 years of age or more are eligible as donors. However, potential donors >50 years will be not eligible if they have more than 2 of the following risk factors; hypertension or serum creatinine >1.5 mg/dl at the time of explantation or an anticipated cold ischemia time of >24 h.
排除标准
- •Patient has previously received any tissue or organ transplant other than the planned kidney graft
- •Female patients who are breast-feeding
- •All female patients of childbearing age* unless the patient is willing to maintain a highly effective method of birth control** for the duration of the study
- •Known contraindication to protocol-specified treatments / medications
- •AL amyloidosis with significant extrarenal involvement
- •Decompensated cirrhosis
- •Severe irreversible obstructive or restrictive lung disease
- •Severe uncorrectable and symptomatic cardiac disease that is deemed by cardiologists to preclude transplantation
- •Progressive central neurodegenerative disease
- •Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up visit schedule
- •Any form of drug or alcohol abuse, psychiatric disorder, or other condition that, in the opinion of the Investigator, may invalidate communication with the Investigator and/or designated study personnel
- •HIV-positive or suffering chronic viral hepatitis
- •Patients unable to give their informed consent (e.g. patients under legal guardianship)
- •Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
- •Known allergy/hypersensitivity to any component of the study product
- •Positive SARS-CoV-2 RT-PCR test
- •Persons who demonstrate dependency from the sponsor, investigator or trial site
- •Panel-reactive antibodies (PRA) grade > 20% within last 6 months before enrolment
- •Previous treatment with any desensitization procedure with or without intravenous immunoglobulin
- •Concomitant malignancy or history of malignancy within 5 years prior to study inclusion in the trial (excluding successfully-treated non-metastatic basal/squamous cell carcinoma of the skin or curatively treated renal cell carcinoma with complete nephrectomy)
- •Evidence of significant local or systemic infection
- •EBV-negative recipient receiving a kidney from an EBV-positive deceased-donor
- •Significant liver disease, defined as persistently elevated AST and/or ALT levels > 2 x ULN (Upper Limit of Normal range)
- •Malignant or pre-malignant haematological conditions. Multiple myeloma, light or heavy chain deposition disease
- •Any uncontrolled medical condition or concurrent disease that could interfere with the study objectives
- •Any condition which, according to the PI, would place the subject at undue risk
- •Ongoing treatment with systemic immunosuppressive drugs at study entry
- •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
- •Female patients of childbearing age with a positive pregnancy test at enrolment
研究组 & 干预措施
Advagraf 1 mg prolonged-release hard capsules, Urbason 4 mg Tabletten, Envarsus 1 mg prolonged-release tablets, Urbason solubile forte 250 mg Pulver und Lösungsmittel zur Herstellung einer Injektionslösung/Infusionslösung, Prograf 0,5 mg Hartkapseln, Treg02, CellCept 500 mg film-coated tablets
干预措施: Advagraf 1 mg prolonged-release hard capsules (Drug)
Advagraf 1 mg prolonged-release hard capsules, Urbason 4 mg Tabletten, Envarsus 1 mg prolonged-release tablets, Urbason solubile forte 250 mg Pulver und Lösungsmittel zur Herstellung einer Injektionslösung/Infusionslösung, Prograf 0,5 mg Hartkapseln, Treg02, CellCept 500 mg film-coated tablets
干预措施: Urbason 4 mg Tabletten (Drug)
Advagraf 1 mg prolonged-release hard capsules, Urbason 4 mg Tabletten, Envarsus 1 mg prolonged-release tablets, Urbason solubile forte 250 mg Pulver und Lösungsmittel zur Herstellung einer Injektionslösung/Infusionslösung, Prograf 0,5 mg Hartkapseln, Treg02, CellCept 500 mg film-coated tablets
干预措施: Envarsus 1 mg prolonged-release tablets (Drug)
Advagraf 1 mg prolonged-release hard capsules, Urbason 4 mg Tabletten, Envarsus 1 mg prolonged-release tablets, Urbason solubile forte 250 mg Pulver und Lösungsmittel zur Herstellung einer Injektionslösung/Infusionslösung, Prograf 0,5 mg Hartkapseln, Treg02, CellCept 500 mg film-coated tablets
干预措施: Urbason solubile forte 250 mg Pulver und Lösungsmittel zur Herstellung einer Injektionslösung/Infusionslösung (Drug)
Advagraf 1 mg prolonged-release hard capsules, Urbason 4 mg Tabletten, Envarsus 1 mg prolonged-release tablets, Urbason solubile forte 250 mg Pulver und Lösungsmittel zur Herstellung einer Injektionslösung/Infusionslösung, Prograf 0,5 mg Hartkapseln, Treg02, CellCept 500 mg film-coated tablets
干预措施: Prograf 0,5 mg Hartkapseln (Drug)
Advagraf 1 mg prolonged-release hard capsules, Urbason 4 mg Tabletten, Envarsus 1 mg prolonged-release tablets, Urbason solubile forte 250 mg Pulver und Lösungsmittel zur Herstellung einer Injektionslösung/Infusionslösung, Prograf 0,5 mg Hartkapseln, Treg02, CellCept 500 mg film-coated tablets
干预措施: Treg02 (Drug)
Advagraf 1 mg prolonged-release hard capsules, Urbason 4 mg Tabletten, Envarsus 1 mg prolonged-release tablets, Urbason solubile forte 250 mg Pulver und Lösungsmittel zur Herstellung einer Injektionslösung/Infusionslösung, Prograf 0,5 mg Hartkapseln, Treg02, CellCept 500 mg film-coated tablets
干预措施: CellCept 500 mg film-coated tablets (Drug)
Ampho-Moronal Lutschtabletten, Histakut Dimetindenmaleat 1 mg/ml Injektionslösung, Paracetamol-ratiopharm® 1000 mg Tabletten, Valganciclovir-ratiopharm® 450 mg Filmtabletten, Cotrim-ratiopharm® 400 mg/80 mg Tabletten, Thymoglobuline 5 mg/ml, Pulver zur Herstellung einer Infusionslösung.
干预措施: Ampho-Moronal Lutschtabletten (Drug)
Ampho-Moronal Lutschtabletten, Histakut Dimetindenmaleat 1 mg/ml Injektionslösung, Paracetamol-ratiopharm® 1000 mg Tabletten, Valganciclovir-ratiopharm® 450 mg Filmtabletten, Cotrim-ratiopharm® 400 mg/80 mg Tabletten, Thymoglobuline 5 mg/ml, Pulver zur Herstellung einer Infusionslösung.
干预措施: Histakut Dimetindenmaleat 1 mg/ml Injektionslösung (Drug)
Ampho-Moronal Lutschtabletten, Histakut Dimetindenmaleat 1 mg/ml Injektionslösung, Paracetamol-ratiopharm® 1000 mg Tabletten, Valganciclovir-ratiopharm® 450 mg Filmtabletten, Cotrim-ratiopharm® 400 mg/80 mg Tabletten, Thymoglobuline 5 mg/ml, Pulver zur Herstellung einer Infusionslösung.
干预措施: Paracetamol-ratiopharm® 1000 mg Tabletten (Drug)
Ampho-Moronal Lutschtabletten, Histakut Dimetindenmaleat 1 mg/ml Injektionslösung, Paracetamol-ratiopharm® 1000 mg Tabletten, Valganciclovir-ratiopharm® 450 mg Filmtabletten, Cotrim-ratiopharm® 400 mg/80 mg Tabletten, Thymoglobuline 5 mg/ml, Pulver zur Herstellung einer Infusionslösung.
干预措施: Valganciclovir-ratiopharm® 450 mg Filmtabletten (Drug)
Ampho-Moronal Lutschtabletten, Histakut Dimetindenmaleat 1 mg/ml Injektionslösung, Paracetamol-ratiopharm® 1000 mg Tabletten, Valganciclovir-ratiopharm® 450 mg Filmtabletten, Cotrim-ratiopharm® 400 mg/80 mg Tabletten, Thymoglobuline 5 mg/ml, Pulver zur Herstellung einer Infusionslösung.
干预措施: Thymoglobuline 5 mg/ml, Pulver zur Herstellung einer Infusionslösung. (Drug)
Ampho-Moronal Lutschtabletten, Histakut Dimetindenmaleat 1 mg/ml Injektionslösung, Paracetamol-ratiopharm® 1000 mg Tabletten, Valganciclovir-ratiopharm® 450 mg Filmtabletten, Cotrim-ratiopharm® 400 mg/80 mg Tabletten, Thymoglobuline 5 mg/ml, Pulver zur Herstellung einer Infusionslösung.
干预措施: Cotrim-ratiopharm® 400 mg/80 mg Tabletten (Drug)
结局指标
主要结局
Primary safety endpoint 1: Acute toxicity associated with infusion of Treg02, 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, 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 cytomegalovirus (CMV), Epstein-Barr virus (EBV) and polyomavirus reactivation and/or disease, (b) early development of neoplasia
Primary safety endpoint 2: Over-suppression of the immune system by assessing evidence of: (a) major and/or opportunistic infections, especially increased frequency of cytomegalovirus (CMV), Epstein-Barr virus (EBV) and polyomavirus reactivation and/or disease, (b) early development of neoplasia
Primary safety endpoint 3: Chronic toxicity associated with Treg02 infusions, measured by evidence of: (a) malignancies arising directly from adoptive cellular therapy, (b) autoimmune disorders, (c) inflammatory pathologies, (d) anaemia, cytopenia or biochemical anomalies unrelated to the transplanted kidney functions
Primary safety endpoint 3: Chronic toxicity associated with Treg02 infusions, measured by evidence of: (a) malignancies arising directly from adoptive cellular therapy, (b) autoimmune disorders, (c) inflammatory pathologies, (d) anaemia, cytopenia or biochemical anomalies unrelated to the transplanted kidney functions
Primary clinical endpoint: Biopsy-confirmed acute rejection (BCAR) within 60 weeks of organ transplantation
Primary clinical endpoint: Biopsy-confirmed acute rejection (BCAR) within 60 weeks of organ transplantation
次要结局
- Secondary indices of efficacy 1: Prevention of acute rejection (a): time to first acute rejection, b): severity of acute rejection episodes based on response to treatment and histological scoring, c): 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 or interstitial fibrosis/tubular atrophy) assessed by clinically impaired glomerular filtration rate (GFR) and histopathological (Banff staging) criteria measures
- Secondary indices of efficacy 4: Incidence of post-transplant dialysis, inclusion on the transplant waiting list, or re-transplantation following graft loss through rejection (acute or chronic)
- Secondary indices of efficacy 5: 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 regulatory T cells
- Quality-of-life using the SF-12 QoL health survey
研究者
Prof. Dr. med. Petra Reinke
Scientific
Charite Universitaetsmedizin Berlin KöR