美国贝勒·斯科特和怀特健康中心Elizabeth Li研究组取得一项新突破。他们提出了veverimer在慢性肾病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，安慰剂控制，延长40周。 这一研究成果于2019年8月2日发表在国际顶尖学术期刊《柳叶刀》上。

代谢性酸中毒是慢性肾病、cathemes蛋白分解代谢和骨脱矿的并发症，与肾脏的不良预后和死亡率有关。Veverimer是一种非吸收的、不含反离子的高分子候选药物，可选择性地结合并从胃肠道腔中去除盐酸。

研究小组在7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)的29个地点(医院和专科诊所)进行了一项多中心、随机、盲法、安慰剂对照、为期12周的研究。符合条件的患者慢性肾脏疾病(估计肾小球滤过率20 - 40毫升/每分钟1·73 2)和代谢性酸中毒(血清碳酸氢12-20更易/ L),曾完成了12周的父母学习，他们被随机分配(4:3)veverimer(6克/天)或安慰剂口腔sthempensions水和食物。延长实验的参与者继续接受与父母研究相同的治疗任务。主要终点是安全性，次要终点评估了veverimer对血清碳酸氢盐浓度和生理功能的长期影响。安全性分析集定义为所有接受任何剂量研究药物的患者。

参与者于2017年12月20日至2018年5月4日期间进入研究。在研究中随机分配的217名患者(124名veverimer患者和93名安慰剂患者)中，196名患者(114名veverimer患者和82名安慰剂患者)继续他们的盲性随机治疗分配到这个为期40周的延长研究中。与安慰剂相比，过早停用veverimer的患者更少(分别为3%和10%)，而且没有患者因为不良事件而停用veverimer。血清素不良事件发生在接受veverier治疗的2%和安慰剂治疗的5%(其中2例死亡)。肾系统不良事件的报告中，在veverimer组和安慰剂组分别为8%和15%。在52周时(63% vs 38%， p=0·0015)，服用veverimer的患者比服用安慰剂的患者的碳酸氢盐浓度增加(≥4 mmol/L或正常化)，并且从第1周开始的所有时间点，veverimer的碳酸氢盐浓度都高于安慰剂(p < 0·001)。Veverimer改善了患者报告的生理功能(肾脏疾病和生活-生理功能领域的质量)，与安慰剂相比，在治疗结束后12·1点(SE 3·3;术;0·0001)。veverimer vs .安慰剂(p < 0·0001)的重复椅立试验时间提高了4·3秒(1·2)。

研究认为，在慢性肾脏疾病和代谢性酸中毒患者中，veverimer安全有效地纠正了代谢性酸中毒，改善了主观和客观的生理功能测量。

附：英文原文

Title: Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension

Author: Donald E Wesson, Vandana Mathur, Navdeep Tangri, Yuri Stasiv, Dawn Parsell, Elizabeth Li

Issue&Volume: 2 August 2019

Abstract: 

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 ClinicalTrials.gov, number NCT03390842, 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.

DOI: https://doi.org/10.1016/S0140-6736(19)31388-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31388-1/fulltext#