van Groenendael Roger, Beunders Remi, Hofland Jan, Morshuis Wim J, Kox Matthijs, van Eijk Lucas T, Pickkers Peter
Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
JMIR Res Protoc. 2019 Feb 6;8(2):e11441. doi: 10.2196/11441.
The cardiac surgery-induced systemic inflammatory response may induce postoperative hemodynamic instability and impairment of renal function. EA-230, a linear tetrapeptide (A-Q-G-V), is derived from the beta chain of the human chorionic gonadotropin pregnancy hormone. It has shown immunomodulatory and renoprotective effects in several animal models of systemic inflammation. In phase 1 and phase 2a studies, these immunomodulatory effects were confirmed during human experimental endotoxemia, and EA-230 was found to have an excellent safety profile.
The objective of this first in-patient study is to test the safety and tolerability as well as the immunomodulatory and renoprotective effects of EA-230 in a proof-of-principle design in patients with systemic inflammation following on-pump cardiac surgery.
We describe a prospective, randomized, double-blind, placebo-controlled study in which 180 elective patients undergoing on-pump coronary artery bypass grafting, with or without concomitant valve surgery, are enrolled. Patients will be randomized in a 1:1 ratio and will receive either EA-230 (90 mg/kg/hour) or a placebo. These will be infused at the start of the surgical procedure until the end of the use of the cardiopulmonary bypass. The primary focus of this first-in-patient study will be on safety and tolerability of EA-230. The primary efficacy end point is the modulation of the inflammatory response by EA-230 quantified as the change in interleukin-6 plasma concentrations after surgery. The key secondary end point is the effect of EA-230 on renal function. The study will be conducted in 2 parts to enable an interim safety analysis by an independent data monitoring committee at a sample size of 60. An adaptive design is used to reassess statistical power halfway through the study.
This study has been approved by the independent competent authority and ethics committee and will be conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, and European Directive 2001/20/CE regarding the conduct of clinical trials. Results of this study will be submitted for publication in a peer-reviewed scientific journal. Enrollment of this study commenced in July 2016, and results are expected at the end of 2018.
This adaptive phase 2 clinical study is designed to test the safety and tolerability of EA-230 in patients undergoing cardiac surgery. In addition, efficacy end points focused on the effect of the systemic inflammatory response and renal function are investigated.
ClinicalTrials.gov NCT03145220; https://clinicaltrials.gov/ct2/show/NCT03145220 (Archived by WebCite at http://www.webcitation.org/74JPh8GNN).
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11441.
心脏手术引发的全身炎症反应可能导致术后血流动力学不稳定及肾功能损害。EA - 230是一种线性四肽（A - Q - G - V），源自人绒毛膜促性腺激素的β链。在多种全身炎症动物模型中，它已显示出免疫调节和肾脏保护作用。在1期和2a期研究中，这些免疫调节作用在人体实验性内毒素血症期间得到证实，并且发现EA - 230具有良好的安全性。
这项首次针对住院患者的研究旨在通过原则性验证设计，测试EA - 230在体外循环心脏手术后全身炎症患者中的安全性、耐受性以及免疫调节和肾脏保护作用。
我们描述了一项前瞻性、随机、双盲、安慰剂对照研究，纳入180例接受体外循环冠状动脉搭桥术的择期患者，这些患者可伴有或不伴有同期瓣膜手术。患者将按1:1比例随机分组，分别接受EA - 230（90 mg/kg/小时）或安慰剂。在手术开始时输注，直至体外循环使用结束。这项首次针对住院患者的研究的主要重点将是EA - 230的安全性和耐受性。主要疗效终点是EA - 230对炎症反应的调节作用，通过术后白细胞介素 - 6血浆浓度的变化进行量化。关键次要终点是EA - 230对肾功能的影响。该研究将分两部分进行，以便独立数据监测委员会在样本量为60时进行中期安全性分析。采用适应性设计在研究中途重新评估统计效能。
本研究已获得独立主管部门和伦理委员会的批准，并将按照《赫尔辛基宣言》的伦理原则、《药物临床试验质量管理规范》指南以及关于临床试验实施的欧洲指令2001/20/CE进行。本研究结果将提交至同行评审的科学期刊发表。本研究于2016年7月开始招募患者，预计2018年底得出结果。
这项适应性2期临床研究旨在测试EA - 230在心脏手术患者中的安全性和耐受性。此外，还研究了以全身炎症反应和肾功能影响为重点的疗效终点。
ClinicalTrials.gov NCT03145220；https://clinicaltrials.gov/ct2/show/NCT03145220（由WebCite存档于http://www.webcitation.org/74JPh8GNN）。
国际注册报告识别码（IRRID）：DERR1 - 10.2196/11441。
