The CSL112-2001 trial: Safety and tolerability of multiple doses of CSL112 (apolipoprotein A-I [human]), an intravenous formulation of plasma-derived apolipoprotein A-I, among subjects with moderate renal impairment after acute myocardial infarction
The CSL112-2001 trial: Safety and tolerability of multiple doses of CSL112 (apolipoprotein A-I [human]), an intravenous formulation of plasma-derived apolipoprotein A-I, among subjects with moderate renal impairment after acute myocardial infarction
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DOI：
10.1016/j.ahj.2018.11.008
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发表时间：
2019-02-01
影响因子：
4.8
通讯作者：
Merkely, Bela
中科院分区：
文献类型：
--
作者：
Gibson, C. Michael;Kerneis, Mathieu;Merkely, Bela
载脂蛋白A-I（apolipoprotein A-I，CSL 112）是一种血浆来源的载脂蛋白A-I，用于急性心肌梗死（AMI）后早期降低心血管风险。CSL 112的安全性AMI受试者与中度，3期慢性肾脏病（CKD）是unknown.Methods CSL112_2001，一个多中心，安慰剂对照，平行组，双盲，随机2期试验，入选患者与中度CKD在7天内AMI后。根据估计的肾小球滤过率和是否存在需要治疗的糖尿病对入组进行分层。患者以2：1的比例随机接受4次每周一次的CSL 112 6 g或安慰剂输注。共同主要安全性终点为肾脏严重不良事件（SAE）和急性肾损伤，急性肾损伤定义为基线血清肌酐升高>= 26.5 μ mol/L，持续超过24 hours，在治疗期间，共83例患者随机分组（55例CSL 112 vs 28例安慰剂）。与安慰剂组相比，在CSL 112组中未观察到肾脏SAE增加（CSL 112 = 1 [1.9%]，安慰剂= 4 [14.3%]）。同样，未观察到急性肾损伤事件增加（CSL 112 = 2 [4.0%]，安慰剂= 4 [14.3%]）。两组间其他SAE的发生率相似。CSL 112给药导致ApoA-I和胆固醇流出增加，与入选缺血性Syndrome I试验的ApoA-I事件减少的AMI和肾功能正常或2期CKD患者中观察到的结果相似。g剂量的CSL 112，并支持将这些患者纳入一项有把握评估疗效的III期心血管结局试验。
Background CSL112 (apolipoprotein A-I [human]) is a plasma-derived apolipoprotein A-I developed for early reduction of cardiovascular risk following an acute myocardial infarction (AMI). The safety of CSL112 among AMI subjects with moderate, stage 3 chronic kidney disease (CKD) is unknown.Methods CSL112_2001, a multicenter, placebo-controlled, parallel-group, double-blind, randomized phase 2 trial, enrolled patients with moderate CKD within 7 days following AMI. Enrollment was stratified on the basis of estimated glomerular filtration rate and presence of diabetes requiring treatment. Patients were randomized in a 2:1 ratio to receive 4 weekly infusions of CSL112 6 g or placebo. The co-primary safety end points were renal serious adverse events (SAEs) and acute kidney injury, defined as an increase >= 26.5 mu mol/L in baseline serum creatinine for more than 24 hours, during the treatment period.Results A total of 83 patients were randomized (55 CSL112 vs 28 placebo). No increase in renal SAEs was observed in the CSL112 group compared with placebo (CSL112 = 1 [1.9%], placebo = 4 [14.3%]). Similarly, no increase in acute kidney injury events was observed (CSL112 = 2 [4.0%], placebo = 4 [14.3%]). Rates of other SAEs were similar between groups. CSL112 administration resulted in increases in ApoA-I and cholesterol efflux similar to those observed in patients with AMI and normal renal function or stage 2 CKD enrolled in the ApoA-I Event Reducing in Ischemic Syndromes I trial.Conclusions These results demonstrate the acceptable safety of the 6-g dose of CSL112 among AMI subjects with moderate stage 3 CKD and support inclusion of these patients in a phase 3 cardiovascular outcomes trial powered to assess efficacy.