Treatment of Chronic Active Antibody-mediated Rejection With Bortezomib in Kidney Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- histological lesions of humoral rejection and immunodominant donor specific antibody
研究概览
简要总结
The purpose of the study is to assess the efficacy of bortezomib, in association with steroids, plasma exchange, and polyclonal intravenous immunoglobulins, in the treatment of chronic antibody mediated rejection due to donor specific anti-HLA antibodies, in kidney transplant recipients
详细描述
Chronic active antibody-mediated rejection (AMR) is considered as a main cause of late allograft losses in kidney transplant recipients. It is due to the occurrence of de novo donor-specific anti-HLA antibodies (DSA), i.e. antibodies synthetized by the recipient after transplantation against its transplant. There is currently to efficient treatment. The purpose of our study is to determine the efficacy of bortezomib, a proteasome inhibitor, in the treatment of chronic active antibody-mediated rejection, in association with steroids, plasma exchanges, and polyclonal intravenous immunoglobulins. Patients are recipients of a first or a second kidney transplant for more than 3 months. They display de novo DSA i.e. DSA not detected the day of transplantation and in pre-transplant sera.. They display signs of chronic active AMR on kidney biopsy i.e. a glomerulitis (g) + peritubular capillaritis (ptc) Banff score g+ptc ≥ 2, with or without severe chronic glomerulopathy (Banff score cg<3). Kidney biopsy may have been performed systematically or because of: :
- detection of de novo DSA ,
- and /or proteinuria (> 0.5 g/24h)
- and /or slow graft dysfunction protocol biopsy Primary endpoint is a combined endpoint one year after inclusion, consisting of the stabilization of histological lesions on a new kidney biopsy (delta g+ptc ≤1 and delta cg < 1) and a decrease in DSA mean fluorescence intensity > 50%.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •recipients of a first or a second kidney transplant for more than 3 months
- •age over 18 years
- •with de novo donor specific antibodies (DSA), i.e. antibodies not detected the day of transplantation and in pre-transplant sera
- •with histological lesions of chronic active antibody-mediated rejection (glomerulitis + peritubular capillaritis banff score and chronic glomerulopathy (g+ptc ≥ 2) on a graft biopsy performed because of renal function deterioration, proteinuria, detection of de novo DSA, or on a systematic biopsy
- •written informed consent
- •Given the teratogenic risks described in the SPCs of Velcade and Cellcept:
- •Women of child bearing age must have a negative pregnancy test the day of the inclusion and should use at least one effective contraceptive method before start of medication during the treatment and during the study
- •Men old enough to procreate have to use condoms during the treatment and at least 90 days after the last intake of the treatment during the study. Moreover, given SPCs of Cellcept, it is recommended that female partners to use an effective method of contraception treatment and for 90 days after the last mycophenolate intake by the partner male
- •affiliated with social security health insurance
- •patients with cell rejection lesions associated with chronic humoral rejection lesions active may be included in the study. This rejection can be treated with 3 boluses of 500 mg of methyl prednisolone prior to inclusion.
排除标准
- •patient with preformed DSA
- •recipient of a 3rd or 4th kidney transplant
- •recipient of a transplant combined with another not renal organ
- •patient with a history of humoral acute rejection during the current transplantation
- •estimated GFR below 20 ml/min/1,73m2
- •severe transplant glomerulopathy (cg score = 3)
- •severe peripheral neuropathy, thrombopenia < 100 000 mm3 , neutropenia < 1000 mm3 and/or an uncontrolled evolutionary infection
- •chronic active hepatitis B (positive HBs antigen or HBV DNA), positive chronic hepatitis C and/or known HIV infection
- •allergy to bore or bortezomib or to one of the excipient
- •hepatic failure, abnormal liver tests (bilirubin >3N, transaminases >3n), infiltrative pneumopathy, pericarditis
- •risk of non-adherence to treatment or protocol
- •inclusion in another clinical therapeutic trial
研究组 & 干预措施
Bortezomib
Five plasma exchanges, two cycles of bortezomib + dexamethasone, 4 courses of polyclonal intravenous immunoglobulins
干预措施: Bortezomib (Drug)
Control
Five plasma exchanges, dexamethasone, 4 courses of polyclonal intravenous immunoglobulins
干预措施: Plasma exchanges and intravenous immunoglobulins (Drug)
结局指标
主要结局
histological lesions of humoral rejection and immunodominant donor specific antibody
时间窗: one year
Between inclusion biopsy and end of study biopsy delta g+ptc ≤1 and delta cg \< 1 (Banff score of glomerulitis (g) capillaritis (ptc) and chronic allograft glomerulopathy (cg) Between inclusion and end of study, decrease in mean fluorescence intensity (MFI) of the immunodominant donor specific anti-HLA antibody (DSA with the highest MFI) by Luminex greater than 50%
次要结局
- all donor specific antibodies at one year(one year)
- all donor specific antibodies(6 months)
- Histological lesions(one year)
- renal function and proteinuria(one year)
- Safety of bortezomib in renal transplant recipients(one year)
- Patient and graft survival(one year)
- T and B lymphocytes subsets with bortezomib(one year)
- histological lesions of humoral rejection(one year)
- immunodominant donor specific antibody(one year)