RATIONALE & OBJECTIVE Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) may offer an alternative erythropoiesis-stimulating agents (ESA) for the treatment of anemia in the setting of CKD. To investigate the efficacy and safety of conversion from long-acting erythropoiesis-stimulating agent (ESA) methoxy polyethylene glycol-epoetin beta (MPG-EPO) to the oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) vadadustat 3-times-weekly versus maintenance on MPG-EPO. STUDY DESIGN Phase 3b, open-label, noninferiority trial. SETTING & PARTICIPANTS Multicenter study in United States; 456 patients adults with anemia and dialysis-dependent chronic kidney disease. INTERVENTION Participants were randomized 1:1:1 either to vadadustat (starting dose: 600 mg thrice weekly), vadadustat (starting dose: 900 mg thrice weekly), or MPG-EPO, for up to 52 treatment weeks and 4 safety follow-up weeks after the end of treatment or early termination. OUTCOMES Primary and secondary efficacy endpoints were the mean change in hemoglobin from baseline during primary (weeks 20-26) and secondary (weeks 46-52) evaluation periods, respectively. Noninferiority was specified as a lower bound of the 95% CI above -0.75 g/dL for the difference in mean change in hemoglobin from baseline. Other efficacy endpoints were the proportion of participants with hemoglobin levels within the target range and the proportions of participants requiring ESA or red blood cell transfusion rescue for anemia during the evaluation periods. Transfusion rates were low and occurred at similar rates across treatment groups (2.7% and 4.0% in the combined vadadustat and MPG-EPO groups, respectively). Primary safety endpoints were any treatment-emergent and serious adverse events (AEs). RESULTS After combining the vadadustat groups (600 mg and 900 mg thrice weekly, n=304), vadadustat was noninferior to MPG-EPO (n=152) for both primary (least squares mean treatment difference, -0.33; 95% CI, -0.53 to -0.13) and secondary efficacy endpoints (-0.33; -0.56 to -0.09). Mean hemoglobin concentrations were stable for all groups, except for an initial slight decline in the vadadustat 600 mg group, which stabilized by week 12. ESA rescue for anemia was more frequent in the MPG-EPO group (primary evaluation period, 27.7%; secondary evaluation period, 16.2%) than in the combined vadadustat (14.2%; 7.3%) groups. The incidences of any treatment-emergent and serious treatment-emergent AEs were similar across treatment groups. LIMITATIONS Potential errors in attribution of AEs as drug related. CONCLUSIONS Three-times-weekly vadadustat was noninferior to MPG-EPO on their effect on hemoglobin levels without detectable differences in AEs.

中文翻译：

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Vadadustat 每周 3 次用于透析依赖性 CKD 引起的贫血患者。


基本原理和目标 缺氧诱导因子脯氨酰羟化酶抑制剂（HIF-PHIs）可能为治疗CKD患者的贫血提供了替代的红细胞生成刺激剂（ESA）。探讨从长效红细胞生成刺激剂 （ESA） 甲氧基聚乙二醇-促红细胞生成素 β （MPG-EPO） 转化为口服缺氧诱导因子脯氨酰羟化酶抑制剂 （HIF-PHI） vadadustat 每周 3 次与维持 MPG-EPO 的疗效和安全性。研究设计 3b 期、开放标签、非劣效性试验。地点和参与者 在美国进行的多中心研究;456 名患有贫血和透析依赖性慢性肾病的成人患者。干预 参与者以 1：1：1 的比例随机分配到 vadadustat（起始剂量：600 毫克，每周三次）、vadadustat（起始剂量：900 毫克，每周三次）或 MPG-EPO，最多治疗 52 个治疗周和 4 个安全随访周治疗结束或提前终止。结果 主要和次要疗效终点分别是主要 （第 20-26 周） 和次要 （第 46-52 周） 评估期间血红蛋白相对于基线的平均变化。非劣效性定义为血红蛋白平均变化相对于基线差异的 95% CI 下限高于 -0.75 g/dL。其他疗效终点是血红蛋白水平在目标范围内的参与者比例，以及评估期间需要 ESA 或红细胞输血抢救治疗贫血的参与者比例。输血率低，并且各治疗组之间的输血率相似 （vadadustat 和 MPG-EPO 联合组分别为 2.7% 和 4.0%）。主要安全终点是任何治疗中出现的严重不良事件 （AEs）。 结果在合并 vadadustat 组 （600 mg 和 900 mg，每周 3 次，n=304） 后，vadadustat 在主要终点（最小二乘平均治疗差异，-0.33;95% CI，-0.53 至 -0.13）和次要疗效终点（-0.33;-0.56 至 -0.09）方面均不劣于 MPG-EPO （n=152）。所有组的平均血红蛋白浓度均稳定，但 vadadustat 600 mg 组最初略有下降，到第 12 周趋于稳定。MPG-EPO 组 （主要评估期，27.7%;次要评估期，16.2%） 的贫血 ESA 抢救比联合 vadadustat 组 （14.2%;7.3%） 更频繁。治疗组之间任何治疗中出现的 AE 和严重治疗中出现的 AE 的发生率相似。局限性 将 AE 归因为药物相关的潜在错误。结论 每周 3 次 vadadustat 对血红蛋白水平的影响不劣于 MPG-EPO，AE 无可检测的差异。