持续性红细胞生成素受体激活剂静脉给药在慢性肾脏病透析患者中纠正贫血的疗效、安全性和耐受性

Efficacy, safety and tolerance of continuous erythropoietin receptor activator intravenous administration on anemia correction in dialysis patients with chronic renal anemia

目的评估持续性红细胞生成素受体激活剂（CERA）每2周1次静脉给药与红细胞生成素13（EPO-β）相比在慢性肾脏病（CKD）透析患者中纠正贫血的疗效和安全性。方法采用开放、随机、平行、阳性对照、多中心临床试验方法。正在接受血液透析或腹膜透析且8周内未接受红细胞生成刺激剂（ESA）治疗的CKD贫血成年患者，随机（1：1）接受CERA每2周1次静脉注射（CERA组，n=132例）或EPO-β每周3次静脉注射（EPO组，n=133例）持续治疗24周（包括16周纠正期和8周疗效评估期）。此后对达到目标血红蛋白（Hb）值（定义为首次给药后24周内在未输注红细胞的情况下，Hb≥110g／L且与基线值相比上升≥10g／L）的患者继续分别维持CERA或EPO-β治疗28周，以观察长期安全及耐受性。CERA的起始剂量为0．4μg／k。主要研究终点为前24周的Hb反应率及评估期（17-24周）Hb与基线值相比的变化。结果共计232例患者（87．5％）完成了前24周的治疗，198例患者（74．7％）完成了整个研究（52周）的治疗。CERA治疗组前24周的Hb反应率为87．12％[95％CI（80．2％-92．3％）]。根据其95％CI的下限高于60％（P〈0．01），认为CERA每2周1次静脉给药能有效纠正CKD贫血。符合方案（PP）人群中CERA组与EPO组评估期Hb相对基线变化的差异为-4．7g／L[95％CI（-7．38g／L-1．92g／L）]。根据其95％CI的下限大于预先设定的非劣效性界值-7．5g／L（P=0．0205），认为CERA纠正CKD贫血后维持Hb非劣效于EPO-β。在28周的延长期间两组的Hb水平均保持稳定。研究期间CERA组和EPO组的安全性结果相当，分别有50．0％及54．6％的患者报告了至少1件不良事件（AE），AE与研究人群的特征一致。结论在未接受ESA治疗的CKD透析患者中，每两周静脉注射1次CERA可有效纠正贫血，且纠正贫血后维持Hb非劣效于EPO-β治疗。CKD透析患者对于长期静脉注射给药CERA总体上耐受性良好。

Objective To evaluate the efficacy, safety and tolerance of continuous erythropoietin receptor activator （CERA） once every 2 weeks intravenous injection on anemia correction in dialysis patients compared to Epoetin-β （EPO-[3） administration. Methods An open-label, randomized, parallel, active- control and multi- center clinical trial was performed. All the hemodialysis or peritoneal dialysis patients with chronic renal anemia who had not been treated with erythropoiesis-stimulating agents （ESAs） for at least 8 weeks before entering the treatment phase were randomized （1 ： 1） to receive either CERA once every 2 weeks intravenous administration （CERA group, n=132） or intravenous EPO-β three times weekly （EPO group, n=133） for 24 weeks including 16-week correction period and 8-week efficacy evaluation period. At week 25, the patients who reached the target Hb （defined as Hb ≥ 110 g/L and increase in Hb ≥ 10 g/L from baseline without red blood cell transfusion during the 24 weeks after the first dose） were kept on CERA or EPO-β treatment regimen for the subsequent 28 weeks to evaluate the long-term safety and tolerability. The starting dose of CERA was 0.4μg/kg. Two primary endpoints were （1） the Hb response rate during the first 24 weeks; and （2）the mean change in Hb between the baseline and the evaluation periods （week 17 to week 24）. Results Totally 232 patients （87.5%） completed the first 24- week treatment and 198 patients （74.7%） completed the whole study treatment （52 weeks）. The response rate in CERA group during the first 24 weeks was 87.12%[95% CI（80.2% to 92.3%）]. Since the lower limit of the 95%CI was greater than 60% （P 〈 0.01）, CERA once every 2 weeks intravenous administration was considered as effective in correction of renal anemia. The difference between CERA group and EPO group in mean change of Hb from evaluation periods to baseline in the per-protocol （PP） population was -4.7 g/L [95%CI （-7.38 g/L to -1.92 g/L）]. Since the lower limit of 95%CI was greater than the pre-defined non- inferiority margin -7.5 g/L （P=0.0205）, CERA was considered as non-inferior to EPO in the maintenance of Hb after anemia correction. The Hb level remained stable during the subsequent 28- week extension period in both CERA and EPO groups. During the whole study period, the overall safety findings were similar in CERA and EPO groups, 50.0% and 54.6% of patients experienced at least one adverse event （AE） respectively. The findings from AEs were in accordance with the characteristics of the studied population. Conclusions Intravenous CERA once every 2 weeks is safe and effective for correcting anemia in dialysis patients. Treatment with CERA once every 2 weeks is also non-inferior to 3 times weekly EPO in maintaining the Hb level after the correction. In general, long-term intravenous administration of CERA is well tolerated by dialysis patients with chronic renal anemia.