Department of Cardiovascular Medicine, Kawaguchi Cardiovascular and Respiratory Hospital, Saitama, Japan.
Headquarters of Clinical Development, Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan.
ESC Heart Fail. 2022 Oct;9(5):3275-3286. doi: 10.1002/ehf2.14021. Epub 2022 Jul 6.
This multicentre, randomized, controlled, double-blind, parallel-group Phase III study was conducted to confirm the non-inferiority of OPC-61815 (tolvaptan sodium phosphate) intravenous injections to oral tolvaptan tablets in patients with congestive heart failure and volume overload despite receiving diuretics other than vasopressin antagonists.
Congestive heart failure patients with volume overload despite receiving diuretics other than vasopressin antagonists were randomly assigned (1:1) to receive OPC-61815 (16-mg injection; n = 149) or oral tolvaptan (15-mg tablet; n = 145) once daily for 5 days. Most patients were male; the mean age and weight were 74.7 years and 62.1 kg, respectively; other demographic and clinical characteristics were similar between groups. In this study, the primary endpoint was the change in body weight from baseline to the day after the last dose. Secondary endpoints included improvement from baseline in congestive findings and New York Heart Association classification. The change in body weight was -1.67 kg [95% confidence interval (CI): -1.93, -1.41] and -1.36 kg (95% CI: -1.62, -1.10) in the OPC-61815 group and tolvaptan group, respectively; the difference in the least squares mean between the groups was -0.31 kg (95% CI: -0.68, 0.06). Given the upper CI did not exceed the pre-specified limit of 0.48, this confirmed the non-inferiority of injectable OPC-61815 to oral tolvaptan. Daily urine volume and daily fluid intake increased, and daily fluid balance was negative throughout the treatment period; changes were similar for both groups. All evaluated congestive symptoms and New York Heart Association classifications showed improvement and safety findings were similar between the groups. The incidence of hyperkalaemia was higher in the OPC-61815 group, and the incidence of thirst and dry mouth was higher in the tolvaptan group. Most treatment-emergent adverse events were mild to moderate; one serious treatment-emergent adverse event of hyperkalaemia in the OPC-61815 group was considered treatment related.
OPC-61815 (16-mg injection) was confirmed as non-inferior to oral tolvaptan (15-mg tablet) in patients with congestive heart failure and inadequate response to diuretics; no new safety concerns were observed.
本项多中心、随机、对照、双盲、平行分组 III 期研究旨在确认与口服托伐普坦片相比，OPC-61815（磷酸托伐普坦钠）静脉注射剂在接受除血管加压素拮抗剂以外的利尿剂治疗但仍存在充血性心力衰竭和容量超负荷的患者中不劣效。
接受除血管加压素拮抗剂以外的利尿剂治疗但仍存在充血性心力衰竭和容量超负荷的患者被随机分配（1:1）接受 OPC-61815（16mg 注射剂；n=149）或口服托伐普坦（15mg 片剂；n=145），每日 1 次，连续 5 天。大多数患者为男性；平均年龄和体重分别为 74.7 岁和 62.1kg；两组间其他人口统计学和临床特征相似。在这项研究中，主要终点是从基线到最后一次给药后一天的体重变化。次要终点包括充血性发现和纽约心脏协会（NYHA）分级自基线的改善。OPC-61815 组和托伐普坦组的体重变化分别为-1.67kg（95%置信区间[CI]：-1.93，-1.41）和-1.36kg（95%CI：-1.62，-1.10）；组间最小二乘均值差异为-0.31kg（95%CI：-0.68，0.06）。由于上限 CI 未超过预设的 0.48 限值，因此证实了可注射的 OPC-61815 与口服托伐普坦等效。整个治疗期间，每日尿量和每日液体摄入量增加，每日液体平衡为负值；两组变化相似。所有评估的充血症状和 NYHA 分级均显示改善，两组间安全性结果相似。OPC-61815 组高钾血症的发生率较高，托伐普坦组口渴和口干的发生率较高。大多数治疗后出现的不良事件为轻至中度；OPC-61815 组 1 例严重的治疗后出现的高钾血症不良事件被认为与治疗相关。
OPC-61815（16mg 注射剂）在接受利尿剂治疗但仍存在充血性心力衰竭和对利尿剂反应不足的患者中被证实与口服托伐普坦（15mg 片剂）不劣效；未观察到新的安全性问题。
