背景:肾移植中的慢性活性抗体介导的排斥反应(caAMR)与不可逆的组织损伤有关,并且是长期移植物丢失的主要原因。然而,迄今为止,caAMR的治疗仍是一个挑战.最近,托珠单抗,针对人白细胞介素-6(IL-6)受体的重组人源化单克隆抗体,在治疗CaAMR方面表现出了希望。然而,到目前为止,尚未进行系统研究,强调需要在该领域进行随机对照研究。
方法:INTERCEPT研究是一项研究者驱动的在肾移植受者中进行的随机对照开放标签多中心试验,以评估托珠单抗治疗活检证实的caAMR的疗效。移植后至少12个月,总共50名接受活检证实的caAMR的接受者将被随机分配接受加入我们的标准护理(SOC)维持治疗的托珠单抗(n=25)或单独的SOC(n=25),为期24个月。在停止研究药物治疗后,患者将再随访12个月。在基线时进行包涵体活检后,方案肾移植活检将在12和24个月进行。样本量计算假设两组之间的估计肾小球滤过率(eGFR)斜率差异为5ml/年,功率为80%,α为0.05。主要终点是开始治疗后24个月eGFR的斜率。次要终点包括12、24和36个月时的以下评估:综合风险评分iBox,安全,供体特异性抗体(DSA)的进化和特征,移植物组织学,蛋白尿,通过测量GFR(mGFR)评估肾功能,患者和死亡审查的移植物存活率,和患者报告的结果,包括移植特异性健康,对免疫抑制药物的依从性和对移植物排斥风险的感知威胁。
结论:目前尚无有效的治疗方法。基于托珠单抗抑制IL-6受体将减少抗体产生并减少抗体介导的损伤的假设,我们的随机试验有可能为caAMR的新治疗策略提供证据,从而在长期内减缓移植物功能的下降。
背景:ClinicalTrials.govNCT04561986。于2020年9月24日注册。
BACKGROUND: Chronic active antibody-mediated rejection (caAMR) in kidney transplants is associated with irreversible tissue damage and a leading cause of graft loss in the long-term. However, the treatment for caAMR remains a challenge to date. Recently, tocilizumab, a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor, has shown promise in the treatment of caAMR. However, it has not been systematically investigated so far underscoring the need for randomized controlled studies in this area.
METHODS: The INTERCEPT study is an investigator-driven randomized controlled open-label multi-center trial in kidney transplant recipients to assess the efficacy of tocilizumab in the treatment of biopsy-proven caAMR. A total of 50 recipients with biopsy-proven caAMR at least 12 months after transplantation will be randomized to receive either tocilizumab (n = 25) added to our standard of care (SOC) maintenance treatment or SOC alone (n = 25) for a period of 24 months. Patients will be followed for an additional 12 months after cessation of study medication. After the inclusion biopsies at baseline, protocol kidney graft biopsies will be performed at 12 and 24 months. The sample size calculation assumed a difference of 5 ml/year in slope of estimated glomerular filtration rate (eGFR) between the two groups for 80% power at an alpha of 0.05. The primary endpoint is the slope of eGFR at 24 months after start of treatment. The secondary endpoints include assessment of the following at 12, 24, and 36 months: composite risk score iBox, safety, evolution and characteristics of donor-specific antibodies (DSA), graft histology, proteinuria, kidney function assessed by measured GFR (mGFR), patient- and death-censored graft survival, and patient-reported outcomes that include transplant-specific well-being, adherence to immunosuppressive medications and perceived threat of the risk of graft rejection.
CONCLUSIONS: No effective treatment exists for caAMR at present. Based on the hypothesis that inhibition of IL-6 receptor by tocilizumab will reduce antibody production and reduce antibody-mediated damage, our randomized trial has a potential to provide evidence for a novel treatment strategy for caAMR, therewith slowing the decline in graft function in the long-term.
BACKGROUND: ClinicalTrials.gov NCT04561986. Registered on September 24, 2020.