Background:Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI.Methods:This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments.Results:A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P=0.02; odds ratio, 0.58 (95% CI, 0.37–0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment.Conclusions:The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897).Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02610283.

中文翻译：

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Teprasiran，一种小干扰 RNA，用于预防接受心脏手术的高危患者的急性肾损伤：一项随机临床研究

背景：急性肾损伤 (AKI) 影响多达 30% 的接受心脏手术的患者，导致住院和长期发病率和死亡率增加。Teprasiran 是一种新型小干扰 RNA，可暂时抑制 P53 介导的细胞死亡，这是 AKI 的基础。 teprasiran 与安慰剂 (1:1) 相比，在降低高危患者心脏手术后 AKI 的发生率、严重程度和持续时间方面。主要终点是术后第 5 天通过血清肌酐确定的发生 AKI 的患者比例。其他终点包括使用各种预先指定标准的 AKI 严重程度和持续时间。为未来的临床开发提供信息，评估了第 90 天主要不良肾脏事件的复合终点，包括死亡、肾脏替代治疗和估计肾小球滤过率降低≥25%。血清肌酐和血清胱抑素-C 均用于估计肾小球滤过率评估。结果：共有 360 名患者被随机分配到 41 个中心；341 名给药患者的年龄为 73±7.5 岁（平均值±标准差），72% 为男性，欧洲心脏手术风险评估系统的中位数为 2.6%。组间人口统计学和手术参数相似。替普拉西兰组 AKI 发生率为 37%，安慰剂组为 50%，绝对风险降低 12.8%，血清肌酐和血清胱抑素-C 均用于估计肾小球滤过率评估。结果：共有 360 名患者被随机分配到 41 个中心；341 名给药患者的年龄为 73±7.5 岁（平均值±标准差），72% 为男性，欧洲心脏手术风险评估系统的中位数为 2.6%。组间人口统计学和手术参数相似。替普拉西兰组 AKI 发生率为 37%，安慰剂组为 50%，绝对风险降低 12.8%，血清肌酐和血清胱抑素-C 均用于估计肾小球滤过率评估。结果：共有 360 名患者被随机分配到 41 个中心；341 名给药患者的年龄为 73±7.5 岁（平均值±标准差），72% 为男性，欧洲心脏手术风险评估系统的中位数为 2.6%。组间人口统计学和手术参数相似。替普拉西兰组 AKI 发生率为 37%，安慰剂组为 50%，绝对风险降低 12.8%，组间人口统计学和手术参数相似。替普拉西兰组 AKI 发生率为 37%，安慰剂组为 50%，绝对风险降低 12.8%，组间人口统计学和手术参数相似。替普拉西兰组 AKI 发生率为 37%，安慰剂组为 50%，绝对风险降低 12.8%，磷=0.02; 优势比，0.58（95% CI，0.37–0.92）。teprasiran 也改善了 AKI 的严重程度和持续时间：2.5% 的 teprasiran-vs 6.7% 的安慰剂治疗患者患有 3 级 AKI；7% teprasiran 和 13% 安慰剂治疗患者的 AKI 持续了 5 天。在第 90 天复合时，总体人群中的主要不良肾脏事件未观察到显着差异。teprasiran 治疗未发现安全问题。结论：teprasiran 给药后，接受心脏手术的高危患者早期 AKI 的发生率、严重程度和持续时间显着降低。基于这些发现 (NCT03510897) 设计了一项在第 90 天主要结局为主要不良肾脏事件的 3 期研究，该研究最近已完成注册。注册：URL：https://www.clinicaltrials.gov；唯一标识符：