Screening for Subclinical Antibody Mediated Rejection and Efficacy of Belatacept in the Context of de Novo Donor Specific Antibody After Kidney Transplantation (BELA-M-R)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 290
- 试验地点
- 1
- 主要终点
- The efficacy of belatacept combined with standard of care, compared to calcineurin inhibitors (CNI) combined with standard of care, among kidney transplant recipients with sABMR
研究概览
简要总结
Antibody mediated rejection (ABMR) is a major cause of graft loss after kidney transplantation (KT) and is mainly associated with preformed anti-HLA donor specific antibodies (DSAs) (phenotype 1) or de novo DSAs (dnDSAs) (phenotype 2). Preexisting DSA-associated ABMR have superior graft survival compared with dnDSA-associated ABMR, which could partly be explained by the fact that patients with de novo DSA-associated ABMR have biopsy later, when graft dysfunction and/or proteinuria are already present. ABMR is a progressive process with an early stage called subclinical ABMR (sABMR), in which histological lesions are present in the kidney graft without clinical graft dysfunction. These early lesions are now well recognized as risk factors for transplant glomerulopathy and poor graft survival in phenotype 1 ABMR (ref 5). The impact of sABMR associated with dnDSA at any time post-transplant has been less studied and reported. Recently, a retrospective multicenter study was published, within the Spiesser Group that included 123 patients without graft dysfunction who underwent graft biopsy because of the presence of dnDSA (One Lambda, MFI > 1000). Performing a kidney graft biopsy after dnDSA indentification without renal dysfunction leads to the diagnosis of active sABMR in 35 % of cases. Nevertheless, no effect of standard of care treatment in active sABMR was observed. Very recently, an expert consensus for the recommended treatment for ABMR after KT was published. It was conclude that the clear lack of evidence but a standard of care for ABMR was nevertheless defined. Therefore, the current proposal is to evaluate a new strategy for active sABMR, testing a conversion from calcineurin inhibitor (CNI) to belatacept associated with the recently recommended standard of care (SOC) compared to continuing CNI. Belatacept might help to manage nonadherence, decrease the toxicity of CNI on an endothelium already affected by microvascular inflammation, and reduce DSA titers.
The monitoring of dnDSA after KT and an indication graft biopsy in case of appearance, even in the absence of graft dysfunction, is not part of a routine clinical practice in all KT centers. This strategy could be a valuable option, in order to begin treatment of ABMR before graft dysfunction occurs, and therefore to improve prognosis associated with phenotype 2 ABMR. Parajuli et al.4 suggested that early diagnosis and treatment of sABMR with SOC, using DSA monitoring may improve outcomes after KT, but this is a retrospective and no-randomized study. This study will be the first prospective randomized study in the context of de novo DSA. The objective is to evaluate a new combination of treatment for ABMR in the context of dnDSA with subclinical lesions and in the same time may help to determine the real incidence of sABMR in KT recipients with subclinical dnDSA. The use of belatacept in the context of sABMR to improve the non-adherence and to decrease the endothelial toxicity had never been evaluated in a prospective way.
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
- •Screening inclusion criteria:
- •Kidney transplant recipient
- •De novo DSA (MFI > 1000 using the Luminex single antigen beads assay or positive with the manufacturer criteria according to the Luminex assay) absent on the day of kidney transplantation and in the sera prior to kidney transplantation
- •No clinical graft dysfunction at time of DSA detection (< 20 % variation of eGFR compared to last 3 months before detection and < 0,5 g/g proteinuria/creatinuria ratio)
- •Affiliation with, or beneficiary of a Social security (national health insurance) category
- •Person having read and understood the information letter and signed the consent form
- •Women of childbearing potential with effective contraception/very-effective contraception (Cf. CTFG) (oestro-progestatives or intra-uterine device or tubal ligation) and a negative blood pregnancy test.
- •Women surgically sterile (absence of ovaries and/or uterus)
- •Postmenopausal women: confirmation diagnostic (non-medically induced amenorrhea for at least 12 months prior to the inclusion visit)
- •Randomization inclusion criteria:
- •Patients with active sABMR, according Banff 2019 classification, with very slight transplant glomerulogathy (cg = 0 or 1).
排除标准
- •Screening exclusion criteria:
- •Specific treatment for DSA occurrence before kidney graft biopsy: IVIG or rituximab or plasmapheresis or immunoabsorption
- •ABO incompatible kidney transplantation
- •Combined transplantation
- •Transplant recipients who are Epstein-Barr virus (EBV) seronegative or serostatus unknown.
- •Hypersensitivity to the active substance or to any of the excipients - Pregnant or parturient or breastfeeding woman or absence of contraception
- •Person deprived of liberty by an administrative or judiciary decision or person placed under judicial protection, under guardianship or supervision
- •Person consenting to the research participating to another trial
- •Medical history or psychological or sensorial abnormality prone to inhibit the subject to understand the conditions required for his/her participation to the protocol or unable him/her to give an informed consent
- •No signed ICF
- •Randomization exclusion criteria:
- •No sABMR or chronic active sABMR (cg > 1) on initial biopsy
- •History of severe opportunistic infection before randomization
- •Acute or chronic infection with HBV, HCV or HIV
- •EBV negative serology
- •History of post-transplant lymphoproliferative disorder.
研究组 & 干预措施
Control
- Control arm: Standard of care treatment (SOC regimen) with Tacrolimus Tacrolimus will be continued until kidney graft survival with objective of whole blood through levels between 6 and 8 ng/mL
干预措施: Standard of care treatment (SOC regimen) with Tacrolimus (Drug)
Experimental
- Experimental arm: conversion to Belatacept CNI will be tapered within 3 months: 75 % of initial dose on the first month, 50 % on the second month, 25 % on the third month, and stopped and a conversion to Belatacept will be performed. It will be administered (6mg/kg) every 2W for the first 2 months and then every month until kidney graft survival.
干预措施: Conversion to Belatacep (Drug)
结局指标
主要结局
The efficacy of belatacept combined with standard of care, compared to calcineurin inhibitors (CNI) combined with standard of care, among kidney transplant recipients with sABMR
时间窗: over 12 months post-biopsy
Proportion in each arm, at 12 months post randomization, of patients with: * decrease eGFR \> 20% at 12 months post randomization, according to CKD-EPI formula * or bad features on 12-month protocol biopsy: cg \> 1 * or chronic active ABMR according Banff 2019 classification, * or \< 50 % MFI reduction of DSA, * or proteinuria/creatinuria ratio \> 0.5 g/g, * or death, * or graft loss.
次要结局
- Presence of chronic active ABMR(at 12 months post biopsy)
- Serum creatinine and calculation of eGFR(12 months and 36 months post biopsy)
- Proteinuria/creatininuria ratio(12 months and 36 months post biopsy)
- Significant Proteinuria(12 months and 36 months post biopsy)
- Presence of Poor Prognostic Histological Features(12 months post biopsy)
- Biopsy-Proven Acute T Cell-Mediated Rejection(From biopsy to 36 months post biopsy)
- Donor-Specific Antibody (DSA) Mean Fluorescence Intensity (MFI)(12 months post-biopsy and 36 months post-randomization)
- Insufficient Reduction in DSA MFI(12 months post biopsy)
- Evaluation of Safety Outcomes (Adverse Events)(Until the end of the study)
- Graft Loss and Death(12 months and 36 months post biopsy)
- Renal Function and Proteinuria According to Initial Biopsy Groups(12 months and 36 months post biopsy)
- Graft Loss and Death According to Initial Biopsy Groups(12 months and 36 months post biopsy)
- Incidence Rate of de novo Subclinical ABMR (sABMR)(From initial biopsy up to 12 months post biopsy)