Background

Metabolic acidosis, a complication of chronic kidney disease, causes protein catabolism and bone demineralisation and is associated with adverse kidney outcomes and mortality. Veverimer, a non-absorbed, counterion-free, polymeric drug candidate selectively binds and removes hydrochloric acid from the gastrointestinal lumen.

Methods

We did a multicentre, randomised, blinded, placebo-controlled, 40-week extension of a 12-week parent study at 29 sites (hospitals and specialty clinics) in seven countries (Bulgaria, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA). Eligible patients were those with chronic kidney disease (estimated glomerular filtration rate 20–40 mL/min per 1·73 m ²) and metabolic acidosis (serum bicarbonate 12–20 mmol/L), who had completed the 12-week parent study, for which they were randomly assigned (4:3) to veverimer (6 g/day) or placebo as oral suspensions in water with food. Participants in the extension continued with the same treatment assignment as in the parent study. The primary endpoint was safety; the four secondary endpoints assessed the long-term effects of veverimer on serum bicarbonate concentration and physical functioning. The safety analysis set was defined as all patients who received any amount of study drug. This trial is registered at , number , and has now completed.

Findings

Participants entered the study between Dec 20, 2017, and May 4, 2018. Of the 217 patients randomly assigned to treatment in the parent study (124 to veverimer and 93 to placebo), 196 patients (114 veverimer and 82 placebo) continued on their blinded randomised treatment assignment into this 40-week extension study. Compared with placebo, fewer patients on veverimer discontinued treatment prematurely (3% vs 10%, respectively), and no patients on veverimer discontinued because of an adverse event. Serious adverse events occurred in 2% of veverimer-treated patients and in 5% of placebo patients (two of whom died). Renal system adverse events were reported in 8% and 15% in the veverimer and placebo groups, respectively. More patients on veverimer than placebo had an increase in bicarbonate (≥4 mmol/L or normalisation) at week 52 (63% vs 38%, p=0·0015) and higher bicarbonate concentrations were observed with veverimer than placebo at all timepoints starting at week 1 (p<0·001). Veverimer resulted in improved patient-reported physical functioning (Kidney Disease and Quality of Life–Physical Function Domain) versus placebo with a mean placebo-subtracted change at end of treatment of 12·1 points (SE 3·3; p<0·0001). Time to do the repeat chair stand test improved by 4·3 s (1·2) on veverimer versus 1·4 s (1·2) on placebo (p<0·0001).

Interpretation

In patients with chronic kidney disease and metabolic acidosis, veverimer safely and effectively corrected metabolic acidosis and improved subjective and objective measures of physical function.

Funding

Tricida.

中文翻译：

---

韦韦莫米在慢性肾脏疾病的代谢性酸中毒患者中的长期安全性和有效性：多中心，随机，盲法，安慰剂对照，延长40周

背景

代谢性酸中毒是一种慢性肾脏疾病的并发症，会引起蛋白质分解代谢和骨骼脱矿质，并与不良的肾脏结局和死亡率相关。Veverimer是一种非吸收性，无抗衡离子的聚合候选药物，可选择性地结合胃肠道腔中的盐酸并从中去除。

方法

我们在七个国家（保加利亚，格鲁吉亚，匈牙利，塞尔维亚，斯洛文尼亚，乌克兰和美国）。符合条件的患者是患有慢性肾脏疾病的患者（估计肾小球滤过率每1·73 m ²为20–40 mL / min）和代谢性酸中毒（血清碳酸氢盐为12–20 mmol / L），他们完成了为期12周的父项研究，并被随机分配（4：3）服用veverimer（6 g /天）或安慰剂作为口服混悬剂。水与食物。扩展中的参与者继续进行与父研究相同的治疗分配。主要终点是安全性；四个次要终点评估了伐韦莫尔对血清碳酸氢盐浓度和身体机能的长期影响。安全性分析集定义为所有接受任何量研究药物的患者。该试用版的注册地址为，编号为，现已完成。

发现

参与者于2017年12月20日至2018年5月4日进入研究。在父项研究中随机分配到治疗的217名患者中（veverimer为124名，安慰剂为93名），196名患者（114名veverimer和82名安慰剂为继续）在这项为期40周的扩展研究中，对随机化的治疗分配不知情。与安慰剂相比，使用veverimer提前终止治疗的患者更少（3％vs分别为10％），并且没有出现因不良事件而停用veverimer的患者。接受veverimer治疗的患者中有2％发生了严重的不良事件，安慰剂患者中有5％发生了严重不良事件（其中两名死亡）。韦弗瑞米组和安慰剂组分别报告有8％和15％的肾脏系统不良事件。在第52周时，使用veverimer的患者比使用安慰剂的患者有更多的碳酸氢盐升高（≥4mmol / L或正常化）（63％vs从第1周开始的所有时间点，观察到veverimer的碳酸氢盐浓度比安慰剂高38％，p = 0·0015（p <0·001）。与安慰剂相比，Veverimer改善了患者报告的身体功能（肾脏疾病和生活质量-身体功能域），在治疗结束时平均减去安慰剂后的变化为12·1点（SE 3·3； p <0·0001） ）。进行重复椅架测试的时间在veverimer上提高了4·3 s（1·2），而在安慰剂上则提高了1·4 s（1·2）（p <0·0001）。

解释

对于患有慢性肾脏疾病和代谢性酸中毒的患者，veverimer安全有效地纠正了代谢性酸中毒并改善了身体功能的主观和客观指标。

资金

特里西达。