一项关于静脉注射FDY - 5301用于接受直接经皮冠状动脉介入治疗的急性ST段抬高型心肌梗死患者的随机、双盲、剂量范围临床试验。
A Randomized, double-blind, dose ranging clinical trial of intravenous FDY-5301 in acute STEMI patients undergoing primary PCI.
作者信息
Adlam David, Zarebinski Maciej, Uren Neal G, Ptaszynski Pawel, Oldroyd Keith G, Munir Shahzad, Zaman Azfar, Contractor Hussain, Kiss Róbert Gábor, Édes István, Szachniewicz Joanna, Nagy Gergely Gyorgy, Garcia Mario J, Tomcsanyi János, Irving John, Sharp Andrew S P, Musialek Piotr, Lupkovics Géza, Shirodaria Cheerag, Selvanayagam Joseph B, Quinn Pauline, Ng Leong, Roth Mark, Insko Michael A, Haber Ben, Hill Stephen, Siegel Lori, Tulloch Simon, Channon Keith M
机构信息
Department of Cardiovascular Sciences, NIHR Leicester Biomedical Research Centre, University of Leicester, UK.
Invasive Cardiology Dept. Western Hospital, Grodzisk Mazowiecki, Poland.
出版信息
Int J Cardiol. 2022 Jan 15;347:1-7. doi: 10.1016/j.ijcard.2021.11.016. Epub 2021 Nov 12.
BACKGROUND
Ischemia-reperfusion injury remains a major clinical problem in patients with ST-elevation myocardial infarction (STEMI), leading to myocardial damage despite early reperfusion by primary percutaneous coronary intervention (PPCI). There are no effective therapies to limit ischemia-reperfusion injury, which is caused by multiple pathways activated by rapid tissue reoxygenation and the generation of reactive oxygen species (ROS). FDY-5301 contains sodium iodide, a ubiquitous inorganic halide and elemental reducing agent that can act as a catalytic anti-peroxidant. We tested the feasibility, safety and potential utility of FDY-5301 as a treatment to limit ischemia-reperfusion injury, in patients with first-time STEMI undergoing emergency PPCI.
METHODS
STEMI patients (n = 120, median 62 years) presenting within 12 h of chest pain onset were randomized at 20 PPCI centers, in a double blind Phase 2 clinical trial, to receive FDY-5301 (0.5, 1.0 or 2.0 mg/kg) or placebo prior to reperfusion, to evaluate the feasibility endpoints. Participants underwent continuous ECG monitoring for 14 days after PPCI to address pre-specified cardiac arrhythmia safety end points and cardiac magnetic resonance imaging (MRI) at 72 h and at 3 months to assess exploratory efficacy end points.
RESULTS
Intravenous FDY-5301 was delivered before re-opening of the infarct-related artery in 97% participants and increased plasma iodide levels ~1000-fold within 2 min. There was no significant increase in the primary safety end point of incidence of cardiac arrhythmias of concern. MRI at 3 months revealed median final infarct sizes in placebo vs. 2.0 mg/kg FDY-5301-treated patients of 14.9% vs. 8.5%, and LV ejection fractions of 53.9% vs. 63.2%, respectively, although the study was not powered to detect statistical significance. In patients receiving FDY-5301, there was a significant reduction in the levels of MPO, MMP2 and NTproBNP after PPCI, but no reduction with placebo.
CONCLUSIONS
Intravenous FDY-5301, delivered immediately prior to PPCI in acute STEMI, is feasible, safe, and shows potential efficacy. A larger trial is justified to test the effects of FDY-5301 on acute ischemia-reperfusion injury and clinical outcomes.
CLINICAL TRIAL REGISTRATION
CT.govNCT03470441; EudraCT 2017-000047-41.
背景
缺血再灌注损伤仍是ST段抬高型心肌梗死（STEMI）患者的一个主要临床问题，尽管通过直接经皮冠状动脉介入治疗（PPCI）实现了早期再灌注，但仍会导致心肌损伤。目前尚无有效的疗法来限制缺血再灌注损伤，这种损伤是由快速组织再氧合和活性氧（ROS）生成激活的多种途径引起的。FDY-5301含有碘化钠，一种普遍存在的无机卤化物和元素还原剂，可作为催化性抗氧化剂。我们测试了FDY-5301作为一种限制缺血再灌注损伤的治疗方法在接受急诊PPCI的首次STEMI患者中的可行性、安全性和潜在效用。
方法
在20个PPCI中心进行的一项双盲2期临床试验中，将胸痛发作12小时内就诊的STEMI患者（n = 120，中位年龄62岁）随机分组，在再灌注前接受FDY-5301（0.5、1.0或2.0mg/kg）或安慰剂，以评估可行性终点。参与者在PPCI后连续14天进行心电图监测，以确定预先指定的心律失常安全终点，并在72小时和3个月时进行心脏磁共振成像（MRI），以评估探索性疗效终点。
结果
97%的参与者在梗死相关动脉重新开通前静脉注射了FDY-5301，并在2分钟内使血浆碘水平升高了约1000倍。关注的心律失常发生率这一主要安全终点没有显著增加。3个月时的MRI显示，安慰剂组与2.0mg/kg FDY-5301治疗组患者的最终梗死大小中位数分别为14.9%和8.5%，左心室射血分数分别为53.9%和63.2%，尽管该研究的样本量不足以检测统计学显著性。在接受FDY-5301的患者中，PPCI后MPO、MMP2和NTproBNP水平显著降低，但安慰剂组没有降低。
结论
在急性STEMI患者中，PPCI前立即静脉注射FDY-5301是可行、安全的，并显示出潜在疗效。有必要进行更大规模的试验来测试FDY-5301对急性缺血再灌注损伤和临床结局的影响。
临床试验注册
CT.govNCT03470441；EudraCT 2017-000047-41。
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