Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I).
Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I).
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DOI：
10.1161/circulationaha.116.025687
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发表时间：
2016-12-13
期刊：
影响因子：
37.8
通讯作者：
Harrington RA
中科院分区：
文献类型：
--
作者：
Michael Gibson C;Korjian S;Tricoci P;Daaboul Y;Yee M;Jain P;Alexander JH;Steg PG;Lincoff AM;Kastelein JJ;Mehran R;D'Andrea DM;Deckelbaum LI;Merkely B;Zarebinski M;Ophuis TO;Harrington RA
补充数字内容可在文本中找到。人或重组载脂蛋白A-I（apoA-I）在动物和临床研究中已显示出增加高密度脂蛋白介导的胆固醇流出能力并使动脉粥样硬化疾病消退。CSL 112是一种可输注的血浆来源的apoA-I，已在正常受试者或稳定性冠状动脉疾病患者中进行了研究。本研究旨在表征CSL 112在近期急性心肌梗死患者中的安全性、耐受性、药代动力学和药效学。AEGIS-I试验（缺血性综合征I期的Apo-I事件减少）是一项多中心、随机、双盲、安慰剂对照、剂量范围探索的2b期试验。根据肾功能对心肌梗死患者进行分层，并以1：1：1的比例随机分配至CSL 112（2 g apoA-I/剂）和高剂量CSL 112（6 g apoA-I/剂）或安慰剂组，每周输注4次。共同主要安全性终点是发生肝脏安全性事件（丙氨酸转氨酶升高>3倍正常上限或总胆红素升高>2倍正常上限）或肾脏安全性事件（血清肌酐升高>1.5倍基线值或需要新的肾脏替代治疗）。共有1258例患者接受了随机化，91.2%的患者接受了所有4次输注。两个CSL 112组和安慰剂组之间丙氨酸转氨酶或总胆红素升高的发生率差异在方案定义的非劣效性界值4%范围内。同样，血清肌酐升高或新的肾脏替代治疗要求的发生率差异在方案定义的非劣效性界值5%范围内。CSL 112与apoA-I和离体胆固醇流出增加相关，与稳定性冠状动脉疾病患者相似。在次要疗效终点方面，各组之间主要心血管不良事件的复合风险相似。在急性心肌梗死患者中，每4周输注一次CSL 112是可行的，耐受性良好，且与肝或肾功能的任何显著变化或其他安全性问题无关。证实了CSL 112急性增强胆固醇流出的能力。CSL 112在减少重大心血管不良事件方面的潜在获益需要在充分把握度的III期试验中进行评估。URL：https://clinicaltrials.gov。唯一标识符：NCT 02108262。
Supplemental Digital Content is available in the text. Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein–mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial. URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.