日本血液透析慢性肾脏病贫血患者罗沙司他的 3 期、随机、双盲、阳性对照（达贝泊汀α）研究。
Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan.
机构信息
Department of Nephrology, Showa University School of Medicine, Tokyo, Japan
Department of Data Science, Yokohama City University, Yokohama, Japan.
出版信息
J Am Soc Nephrol. 2020 Jul;31(7):1628-1639. doi: 10.1681/ASN.2019060623. Epub 2020 Jun 3.
BACKGROUND
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia.
METHODS
This phase 3, 24-week, double-blind, double-dummy study evaluated roxadustat's noninferiority to darbepoetin alfa for hemodialysis-dependent CKD anemia. We randomly assigned Japanese patients to oral roxadustat three times weekly or to darbepoetin alfa injections once weekly, titrating doses to maintain hemoglobin between 10-12 g/dl. The primary end point was change of average hemoglobin from baseline to weeks 18-24 (Hb). Secondary end points were average hemoglobin and proportion of patients with hemoglobin between 10-12 g/dl (maintenance rate) at weeks 18-24, and iron parameters. Safety assessments included treatment-emergent adverse events and adjudicated ophthalmologic findings.
RESULTS
We randomly assigned 303 patients to roxadustat (=151) or darbepoetin alfa (=152). The difference between roxadustat and darbepoetin alfa in Hb was -0.02 g/dl (95% confidence interval, -0.18 to 0.15), confirming roxadustat's noninferiority to darbepoetin alfa. Average hemoglobin at weeks 18-24 with roxadustat was 10.99 g/dl (95% confidence interval: 10.88 to 11.10), confirming its efficacy. Among patients with one or more hemoglobin value during weeks 18-24, the maintenance rate was 95.2% with roxadustat and 91.3% with darbepoetin alfa. Serum iron, ferritin, and transferrin saturation remained clinically stable with roxadustat; transferrin and total iron binding capacity increased through week 4 before stabilizing. Common treatment-emergent adverse events were nasopharyngitis, shunt stenosis, diarrhea, contusion, and vomiting. The proportion of patients with new or worsening retinal hemorrhage was 32.4% with roxadustat and 36.6% with darbepoetin alfa. We observed no clinically meaningful changes in retinal thickness groups.
CONCLUSIONS
Roxadustat maintained hemoglobin within 10-12 g/dl in patients on hemodialysis and was noninferior to darbepoetin alfa. Treatment-emergent adverse events were consistent with previous reports.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
A Study of Intermittent Oral Dosing of ASP1517 in Hemodialysis Chronic Kidney Disease Patients with Anemia, NCT02952092 (ClinicalTrials.gov).
背景
罗沙司他是一种口服低氧诱导因子脯氨酰羟化酶抑制剂，已在中国获批用于治疗透析依赖型慢性肾脏病贫血。
方法
这是一项 24 周、双盲、双模拟的 3 期研究，评估了罗沙司他治疗透析依赖型慢性肾脏病贫血的非劣效性，与每周一次的注射用达贝泊汀相比。我们将日本患者随机分配至口服罗沙司他每周 3 次或每周一次注射用达贝泊汀治疗，调整剂量以维持血红蛋白在 10-12 g/dl 之间。主要终点为从基线到第 18-24 周时平均血红蛋白的变化（Hb）。次要终点为第 18-24 周时平均血红蛋白和血红蛋白在 10-12 g/dl 之间的患者比例（维持率），以及铁参数。安全性评估包括治疗出现的不良事件和经判定的眼科检查结果。
结果
我们将 303 例患者随机分配至罗沙司他（n=151）或达贝泊汀组（n=152）。罗沙司他和达贝泊汀在 Hb 上的差异为-0.02 g/dl（95%置信区间：-0.18 至 0.15），证实了罗沙司他非劣效于达贝泊汀。罗沙司他在第 18-24 周的平均血红蛋白为 10.99 g/dl（95%置信区间：10.88 至 11.10），证实了其疗效。在第 18-24 周有一次或多次血红蛋白值的患者中，罗沙司他的维持率为 95.2%，达贝泊汀为 91.3%。罗沙司他使血清铁、铁蛋白和转铁蛋白饱和度保持临床稳定；转铁蛋白和总铁结合力在第 4 周前增加，之后稳定。常见的治疗出现的不良事件包括鼻咽炎、分流狭窄、腹泻、挫伤和呕吐。罗沙司他组和达贝泊汀组新发或恶化的视网膜出血患者比例分别为 32.4%和 36.6%。我们观察到视网膜厚度组没有临床意义的变化。
结论
罗沙司他使接受血液透析的患者的血红蛋白维持在 10-12 g/dl 之间，且非劣效于达贝泊汀。治疗出现的不良事件与之前的报告一致。
临床试验注册名称和注册号
间歇性口服 ASP1517 治疗血液透析慢性肾脏病贫血患者的研究，NCT02952092（ClinicalTrials.gov）。
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