Akizawa Tadao, Akiba Takashi, Hirakata Hideki, Kinugasa Eriko, Tominaga Yoshihiro, Fukagawa Masafumi, Yokoyama Keitaro, Zhang Wuyan, Linde Peter G, Suzuki Masashi
Showa University School of Medicine, Tokyo, Japan.
Tokyo Women's Medical University, Tokyo, Japan.
Ther Apher Dial. 2015 Jun;19(3):225-34. doi: 10.1111/1744-9987.12242. Epub 2014 Nov 3.
Secondary hyperparathyroidism (SHPT) is one of the major complications of chronic kidney disease (CKD) and is associated with elevated serum intact parathyroid hormone (iPTH). Calcitriol, a non-selective vitamin D receptor agonist (VDRA) that suppresses iPTH is used for SHPT treatment, but its use is frequently complicated by hypercalcemia. Paricalcitol, a selective VDRA, demonstrated efficacy in iPTH suppression compared to maxacalcitol in a Phase 2 study (M11-609) in Japanese subjects. The current larger Phase 3 study (M11-517), evaluated the efficacy of intravenous paricalcitol injection compared to intravenous maxacalcitol injection with respect to iPTH and calcium control using a non-inferiority primary endpoint. In this double-blind, double-dummy, parallel-group study, eligible Japanese CKD subjects with SHPT on hemodialysis were randomized 1:1 to receive intravenous paricalcitol or intravenous maxacalcitol injections for 12 weeks. Dynamic allocation of subjects on the basis of screening iPTH levels was used to ensure equal distribution of subjects with iPTH <500 pg/mL and ≥500 pg/mL into the two treatment groups. 255 subjects were randomized to receive paricalcitol (N = 127) or maxacalcitol (N = 128). Primary efficacy analysis indicated that 27.7% in the paricalcitol group vs. 30.5% in the maxacalcitol group (95% CI -14.34% to 8.79%, P = 0.353) achieved target iPTH in the last 3 weeks without hypercalcemia during treatment, failing to achieve the non-inferiority margin of -5% that was set based upon agreement with the PMDA. Both intravenous paricalcitol and maxacalcitol were effective in reducing iPTH and provided similar safety profiles; however, non-inferiority for paricalcitol vs. maxacalcitol was not demonstrated.
继发性甲状旁腺功能亢进（SHPT）是慢性肾脏病（CKD）的主要并发症之一，与血清完整甲状旁腺激素（iPTH）升高相关。骨化三醇是一种抑制iPTH的非选择性维生素D受体激动剂（VDRA），用于治疗SHPT，但其使用常并发高钙血症。在一项针对日本受试者的2期研究（M11 - 609）中，与马沙骨化醇相比，选择性VDRA帕立骨化醇在抑制iPTH方面显示出疗效。当前这项规模更大的3期研究（M11 - 517），采用非劣效性主要终点，评估了静脉注射帕立骨化醇与静脉注射马沙骨化醇在控制iPTH和钙方面的疗效。在这项双盲、双模拟、平行组研究中，符合条件的接受血液透析且患有SHPT的日本CKD受试者按1:1随机分组，接受静脉注射帕立骨化醇或静脉注射马沙骨化醇，为期12周。根据筛查时的iPTH水平对受试者进行动态分配，以确保iPTH＜500 pg/mL和≥500 pg/mL的受试者在两个治疗组中均匀分布。255名受试者被随机分配接受帕立骨化醇（N = 127）或马沙骨化醇（N = 128）治疗。主要疗效分析表明，帕立骨化醇组有27.7%的受试者与马沙骨化醇组30.5%的受试者（95%CI -14.34%至8.79%，P = 0.353）在治疗的最后3周内达到目标iPTH且未出现高钙血症，但未达到基于与日本药品和医疗器械管理局（PMDA）达成的协议所设定的-5%的非劣效性界值。静脉注射帕立骨化醇和马沙骨化醇在降低iPTH方面均有效，且安全性相似；然而，未证明帕立骨化醇相对于马沙骨化醇具有非劣效性。
