Zeiher Bernhardt G, Steingrub Jay, Laterre Pierre-Francois, Dmitrienko Alex, Fukiishi Yonetaka, Abraham Edward
Eli Lilly and Company, Indianapolis, IN, USA.
Crit Care Med. 2005 Aug;33(8):1741-8. doi: 10.1097/01.ccm.0000171540.54520.69.
Group IIA secretory phospholipase A2 (sPLA2-IIA), released during inflammation, is increased in severe sepsis, and plasma levels are inversely related to survival. In a previous study, a selective inhibitor of sPLA2-IIA (LY315920NA/S-5920) was well tolerated and appeared to improve survival in a subgroup of patients who received the drug within 24 hrs of first sepsis-induced organ failure. This study was designed to determine whether improvement in survival could be confirmed in a larger patient population meeting the characteristics of that subgroup.
Multicenter, double-blind, placebo-controlled, parallel-group clinical trial of LY315920NA/S-5920 in patients with severe sepsis.
Seventy-five institutions worldwide.
A total of 373 patients with at least two sepsis-induced organ failures.
Patients were randomized 1:1 to receive LY315920NA/S-5920 (target plasma concentration of 800 ng/mL; n = 188) or placebo (n = 185). Study medication was administered as a continuous intravenous infusion for 168 hrs.
The study was terminated after data on 250 patients suggested a significant improvement in 28-day all-cause mortality would not be found if the trial continued as planned. The mortality rate was 39.4% in the LY315920NA/S-5920 group, compared with 31.9% in the placebo group (p = .092). The negative trend in mortality was most pronounced among patients with cardiovascular failure at baseline (41.6% vs. 28.7%; p = .008) and patients whose culture data at baseline were negative (42.9% vs. 22.7%; p = .045). The negative trend in mortality is not explained by adverse events, microbiology, or laboratory data.
Continuous 7-day infusion of an inhibitor of sPLA2-IIA had no beneficial effect on 28-day all-cause mortality among severe sepsis patients with at least two organ failures. This study did not confirm earlier promising subgroup results with LY315920NA/S-5920, which provides a reminder that subgroup effects should be viewed cautiously, especially when primary effects are not significant.
炎症期间释放的IIA组分泌型磷脂酶A2（sPLA2-IIA）在严重脓毒症中升高，且血浆水平与生存率呈负相关。在先前的一项研究中，sPLA2-IIA的选择性抑制剂（LY315920NA/S-5920）耐受性良好，并且似乎能改善在首次脓毒症诱发器官功能衰竭24小时内接受该药物治疗的亚组患者的生存率。本研究旨在确定在符合该亚组特征的更大患者群体中是否能证实生存率有所改善。
LY315920NA/S-5920用于严重脓毒症患者的多中心、双盲、安慰剂对照、平行组临床试验。
全球75家机构。
共有373例至少有两次脓毒症诱发器官功能衰竭的患者。
患者按1:1随机分组，接受LY315920NA/S-5920（目标血浆浓度为800 ng/mL；n = 188）或安慰剂（n = 185）。研究药物通过持续静脉输注给药168小时。
在250例患者的数据提示如果试验按计划继续进行将不会发现28天全因死亡率有显著改善后，该研究提前终止。LY315920NA/S-5920组的死亡率为39.4%，而安慰剂组为31.9%（p = 0.09）。死亡率的负向趋势在基线时有心血管功能衰竭的患者中最为明显（41.6%对28.7%；p = 0.008）以及基线时培养数据为阴性的患者中（42.9%对22.7%；p = 0.045）。死亡率的负向趋势无法用不良事件、微生物学或实验室数据来解释。
连续7天输注sPLA2-IIA抑制剂对至少有两次器官功能衰竭的严重脓毒症患者的28天全因死亡率没有有益影响。本研究未证实LY315920NA/S-5920早期有前景的亚组结果，这提示对于亚组效应应谨慎看待，尤其是在主要效应不显著时。
