达普司他对比阿法达贝泊汀在日本血液透析贫血患者中的疗效和安全性：一项随机、双盲、3 期临床试验。
Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial.
机构信息
Division of Nephrology, Showa University School of Medicine, Tokyo, Japan.
Division of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
出版信息
Clin J Am Soc Nephrol. 2020 Aug 7;15(8):1155-1165. doi: 10.2215/CJN.16011219. Epub 2020 Jul 28.
BACKGROUND AND OBJECTIVES
Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates genes related to iron metabolism. The efficacy (noninferiority) and safety of daprodustat compared with standard therapy (darbepoetin alfa) was evaluated.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a randomized, phase 3, double-blind, active-control study in Japanese patients receiving hemodialysis with anemia of CKD. Participants' treatment was switched from current erythropoiesis-stimulating agents (ESAs) to daprodustat 4 mg once daily or darbepoetin alfa 10-60 g once weekly (on the basis of the prestudy ESA dose). Dose was adjusted every 4 weeks for daprodustat or every 2 weeks for darbepoetin alfa, according to a protocol-specified algorithm. The primary end point was mean hemoglobin during weeks 40-52 in the intent-to-treat population.
RESULTS
Of 332 participants screened, 271 participants were randomized (safety evaluation: 271 participants; efficacy evaluation: 267 intent-to-treat population). The mean hemoglobin during weeks 40-52 were maintained within the target range in both groups (10.9 g/dl [95% confidence interval (95% CI), 10.8 to 11.0] for daprodustat, and 10.8 g/dl [95% CI, 10.7 to 11.0] for darbepoetin alfa). Daprodustat was noninferior to darbepoetin alfa, as the lower bound of the confidence interval for the treatment difference (0.1 g/dl; 95% CI, -0.1 to 0.2 g/dl) was greater than the noninferiority criterion of -1.0 g/dl. For most participants, hemoglobin was maintained within the target range (10.0-12.0 g/dl) during weeks 40-52 (88% daprodustat; 90% darbepoetin alfa). Geometric mean hepcidin levels decreased more at week 52 with daprodustat (-37%; 95% CI, -49 to -23) than with darbepoetin alfa (-20%; 95% CI, -36 to -1), and an increase in total iron-binding capacity was observed in the daprodustat group. Frequency of adverse events were generally similar between daprodustat and darbepoetin alfa.
CONCLUSIONS
Oral daprodustat was noninferior to darbepoetin alfa as measured by mean hemoglobin over weeks 40-52 in Japanese patients receiving hemodialysis switched from ESAs.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
201754, Clinicaltrials.gov, NCT02969655.
背景和目的
达普司他是一种口服低氧诱导因子脯氨酰羟化酶抑制剂，可刺激红细胞生成并调节与铁代谢相关的基因。评估了达普司他与标准治疗（培哚普利）相比的疗效（非劣效性）和安全性。
设计、地点、参与者和测量：这是一项在日本接受血液透析的慢性肾脏病贫血患者中进行的随机、3 期、双盲、活性对照研究。参与者的治疗从当前的促红细胞生成刺激剂（ESA）转换为达普司他 4 毫克，每天一次，或培哚普利 10-60 微克，每周一次（基于研究前 ESA 剂量）。根据协议规定的算法，每 4 周调整一次达普司他或每 2 周调整一次培哚普利的剂量。
主要终点是意向治疗人群中第 40-52 周的平均血红蛋白。
结果
在筛选的 332 名参与者中，有 271 名参与者被随机分组（安全性评估：271 名参与者；疗效评估：267 名意向治疗人群）。两组的平均血红蛋白在第 40-52 周内均维持在目标范围内（达普司他 10.9 g/dl [95%置信区间（95%CI），10.8 至 11.0]，培哚普利 10.8 g/dl [95%CI，10.7 至 11.0]）。达普司他与培哚普利相当，因为治疗差异的置信区间下限（0.1 g/dl；95%CI，-0.1 至 0.2 g/dl）大于-1.0 g/dl 的非劣效性标准。对于大多数参与者，血红蛋白在第 40-52 周内维持在目标范围内（10.0-12.0 g/dl）（达普司他 88%；培哚普利 90%）。第 52 周时，达普司他组的几何平均铁调素水平下降幅度（-37%；95%CI，-49 至-23）大于培哚普利组（-20%；95%CI，-36 至-1），并且达普司他组的总铁结合能力增加。达普司他和培哚普利的不良反应频率通常相似。
结论
在接受血液透析并从 ESA 转换的日本患者中，达普司他的平均血红蛋白在第 40-52 周期间非劣效于培哚普利。
临床试验注册号和名称
201754，Clinicaltrials.gov，NCT02969655。
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