背景:慢性活性抗体介导的排斥反应(AMR)是没有批准的治疗药物的移植物丢失的主要原因。目前,使用标签外方案,反映了基于良好对照试验的有效疗法的高度未满足的需求。Clazakizumab是一种高亲和力,结合白介素-6并减少供体特异性抗体(DSA)产生和炎症的人源化单克隆抗体。clazakizumab在慢性活动性AMR的肾移植受者中的2期初步研究表明DSA的调节,稳定肾小球滤过率(GFR),和可管理的安全档案。我们报告了3期IMAGINE研究(NCT03744910)的设计,以评估clazakizumab治疗慢性活动性AMR的安全性和有效性。
方法:想象是一个多中心,一项针对约350例慢性活动性AMR(班夫慢性肾小球病[cg]>0并发人类白细胞抗原DSA阳性)的肾移植受者的双盲试验,1:1随机分组接受clazakizumab或安慰剂(12.5mg,每4周一次皮下).事件驱动的试验设计将跟踪患者,直到观察到221例全因移植物丢失。定义为返回透析,移植肾切除术,重新移植,估计GFR(eGFR)<15mL/min/1.73m2,或因任何原因死亡。移植物损失的替代(eGFR斜率)将在1年基于先前的建模验证进行评估。次要终点将包括药代动力学/药效学的测量。北美各地正在进行招聘,欧洲,亚洲,和澳大利亚。
结论:IMAGINE代表了第一个3期临床试验,研究了cazakizumab在患有慢性活动性AMR的肾移植受者中的安全性和有效性,以及该患者人群中最大的安慰剂对照试验。该试验包括预后生物标志物富集,并独特地利用1年时的eGFR斜率作为移植物丢失的替代终点,这可能会加速对有移植物丢失风险的患者的新疗法的批准。这项研究的结果将有助于解决慢性活动性AMR新疗法未满足的需求。
背景:ClinicalTrials.govNCT03744910。2018年11月19日注册。
BACKGROUND: Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials.
Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of
clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of
clazakizumab for the treatment of chronic active AMR.
METHODS: IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive
clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia.
CONCLUSIONS: IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of
clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR.
BACKGROUND: ClinicalTrials.gov NCT03744910 . Registered on November 19, 2018.