University of Manitoba, Winnipeg, MB, Canada.
Medical University of Vienna, Vienna, Austria.
Trials. 2022 Dec 22;23(1):1042. doi: 10.1186/s13063-022-06897-3.
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.
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/1.73m, 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.
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.
ClinicalTrials.gov NCT03744910 . Registered on November 19, 2018.
慢性持续性抗体介导的排斥反应（AMR）是导致移植物丧失的主要原因，目前尚无批准用于治疗该病的药物。目前，正在使用未经批准的方案，这反映了基于精心控制的试验的有效治疗方法的巨大需求未得到满足。Clazakizumab 是一种高亲和力的人源化单克隆抗体，可与白细胞介素-6 结合，并减少供体特异性抗体（DSA）的产生和炎症。Clazakizumab 在患有慢性持续性 AMR 的肾移植受者中的 2 期试验表明可调节 DSA、稳定肾小球滤过率（GFR）和可控的安全性。我们报告了 3 期 IMAGINE 研究（NCT03744910）的设计，以评估 clazakizumab 治疗慢性持续性 AMR 的安全性和疗效。
IMAGINE 是一项多中心、双盲试验，约 350 例患有慢性持续性 AMR（Banff 慢性肾小球病[cg] >0 伴同时存在阳性人类白细胞抗原 DSA）的肾移植受者随机 1:1 接受 clazakizumab 或安慰剂（12.5mg 皮下每 4 周一次）。事件驱动的试验设计将在观察到所有原因移植物丢失的 221 个事件之前对患者进行随访，定义为返回透析、移植物肾切除术、再次移植、估计肾小球滤过率（eGFR）<15mL/min/1.73m 或任何原因死亡。根据先前的建模验证，将在 1 年时评估替代移植物丢失的指标（eGFR 斜率）。次要终点将包括药代动力学/药效学测量。北美、欧洲、亚洲和澳大利亚正在进行招募。
IMAGINE 是第一项在患有慢性持续性 AMR 的肾移植受者中研究 clazakizumab 安全性和疗效的 3 期临床试验，也是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，并独特地将 1 年时的 eGFR 斜率用作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型疗法的批准。该研究的结果对于帮助满足对新型慢性持续性 AMR 治疗方法的需求至关重要。
ClinicalTrials.gov NCT03744910 。2018 年 11 月 19 日注册。
