Bortezomib in Late Antibody-mediated Kidney Transplant Rejection (BORTEJECT Study)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 44
- 试验地点
- 1
- 主要终点
- Change of eGFR slopes over time
研究概览
简要总结
Late antibody-mediated rejection (AMR) after kidney transplantation is defined as a separate rejection entity. So far, no appropriate treatment has been established for this rejection type. One promising strategy could be the targeting of alloantibody-producing plasma cells. There is now accumulating evidence that the proteasome inhibitor Bortezomib may substantially affect the function and integrity of non-malignant alloantibody-secreting plasma cells. The impact of this compound on the course of late AMR , however, has not yet been systematically investigated. In the planned phase IIa study we will examine the effect of Bortezomib on late AMR after kidney transplantation. We plan an initial cross-sectional HLA antibody screening of 1000 kidney transplant recipients to identify patients with detectable donor-specific antibodies (DSA). DSA-positive recipients will be subjected to kidney allograft biopsy to detect morphological features consistent with AMR. Forty-four patients with late AMR will be included in a randomized double-blind placebo-controlled parallel-group intervention trial. Patients in the active group will receive two cycles of Bortezomib (4 x 1.3 mg/m2). The primary end point will be the course of estimated GFR over 24 months after randomization. Secondary endpoints are the course of DSA levels and protein excretion, measured GFR after 24 months, transplant and patient survival, and the development of acute and chronic morphological lesions in 24-month protocol biopsies. Our study will clarify the impact of an innovative anti-humoral strategy on the deleterious effects of late AMR processes.
详细描述
Background
Recent studies have underscored a dominant role of alloimmune injury as a leading cause of long-term graft loss in kidney transplantation. In this respect, the formation of antibodies against specific polymorphic donor antigens, commonly human leukocyte antigens (HLA), has turned out to be an important trigger of graft rejection (Colvin, RB et al. 2007).
Humoral rejection (antibody-mediated rejection; AMR) of organ transplants has been established to constitute a separate rejection entity and in recent years accurate biopsy-based (C4d) and serological criteria for this rejection type have been defined to provide a valuable basis for targeted treatment (Sis, B et al. 2010). It has become evident that a considerable proportion of recipients develop features of AMR late after transplantation, a process culminating in chronic irreversible tissue damage, graft dysfunction and loss (Mauiyyedi, S et al. 2001). Indeed, there are studies suggesting that newly formed donor-specific antibodies (DSA) represent the primary cause of late graft loss (Einecke, G et al. 2009).
In contrast to early acute AMR, where various treatment protocols including immunoadsorption, intravenous immunoglobulin (IVIG) or CD20 antibody (Rituximab) exist, appropriate targeted treatment for late AMR still remains to be established (Vo, A et al. 2008).
In an earlier uncontrolled study of 11 kidney transplant recipients with advanced C4d-positive chronic AMR we found that conversion of Cyclosporine A and Azathioprine-based basal immunosuppression to Tacrolimus and Mycophenolate-Mofetil (MMF) did not have any impact on DSA levels and graft performance (Schwarz, C et al. 2006). Our observations, which are in some contrast to a previous small study (Theruvath, TP et al. 2001), suggested that simple conversion strategies may not suffice to ameliorate ongoing late AMR.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Part A (Screening for DSA, cross-sectional)
- •Written informed consent
- •Age > 18 years
- •Functioning allograft after ≥180 days
- •eGFR >20 ml/min/1.73 m2
排除标准
- •Part A (Screening for DSA, cross-sectional)
- •Patients actively participating in another clinical trial
- •Female subject is pregnant or lactating
- •Acute rejection treatment <1 month before screening
- •Acute deterioration of graft function due to suspected acute rejection
- •Active viral, bacterial or fungal infection precluding bortezomib treatment
- •Active malignant disease precluding intensified immunosuppressive therapy
- •Serious medical or psychiatric illness likely to interfere with participation in the study
- •Documented intolerance of Bortezomib, boron or mannitol
- •Inclusion Criteria:
- •Part B (Interventional study)
- •Written informed consent
- •Age > 18 years
- •Functioning allograft after ≥180 days
- •eGFR >20 ml/min/1.73 m2
- •HLA class I and/or II DSA-positive
- •A kidney biopsy result showing Glomerulitis and/or peritubular capillaritis and/or transplant glomerulopathy and/or peritubular capillary (PTC) basement membrane lamellation (with or without C4d in PTC).
- •Exclusion Criteria:
- •Part B (Interventional study)
- •Patients actively participating in another clinical trial
- •Female subject is pregnant or lactating
- •Acute rejection treatment <1 month before screening
- •Acute deterioration of graft function due to suspected acute rejection
- •Active viral, bacterial or fungal infection precluding Bortezomib treatment
- •Active malignant disease precluding intensified immunosuppressive therapy
- •Serious medical or psychiatric illness likely to interfere with participation in the study
- •Documented intolerance of Bortezomib, boron or mannitol
- •Thrombocytopenia <30 G/l within 2 weeks before enrolment
- •Neutrophil count <1 G/l within 2 weeks before enrolment
- •Peripheral neuropathy ≥grade 2
- •T-cell-mediated rejection classified Banff grade >I
- •De novo or recurrent severe thrombotic microangiopathy
- •Polyoma virus nephropathy
- •De novo or recurrent glomerulonephritis in the allograft
研究组 & 干预措施
Placebo (NaCl solution)
Patients will receive two cycles of Placebo (NaCl solution) at an interval of three months.
Each cycle will consist of intravenously administered (within 3-5 seconds) Placebo twice weekly on days 1, 4, 8 and 11.
干预措施: Placebo (Drug)
Bortezomib (Velcade®)
Patients will receive two cycles of Bortezomib (Velcade®) at an interval of three months.
Each cycle will consist of intravenously administered (within 3-5 seconds) Bortezomib 1.3 mg/m2 twice weekly on days 1, 4, 8 and 11.
干预措施: Bortezomib (Drug)
结局指标
主要结局
Change of eGFR slopes over time
时间窗: Change from baseline eGFR at 24 months
Peripheric venous blood samples (4ml) will be obtained after 0, 6, 12, 18 an 24 months to assess the change of eGFR slopes over time. In case of loss of follow-up the GFR is assumed to be 0ml/min.
次要结局
- Change in urine proteine excretion over time(Change from baseline urine proteine excretion at 24 months after randomization)
- Change of HLA antibody (DSA) levels over time(Change from baseline HLA antibody (DSA) level at 24 months)
- Exact measured GFR by Chromium-51 EDTA (Cr-EDTA) clearance method(Change from baseline GFR at 24 months after randomization)
- All-cause mortality(At 24 months after randomization)
- Graft loss(At 24 months after randomization)
研究者
Farsad Eskandary
Farsad Eskandary, MD
Medical University of Vienna