Alpert Medical School of Brown University, Providence, Rhode Island, USA.
JAMA. 2013 Mar 20;309(11):1154-62. doi: 10.1001/jama.2013.2194.
Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response.
To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality.
DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011.
Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively.
The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment.
Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, -1.1; 95% CI, -5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups.
Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality.
clinicaltrials.gov Identifier: NCT00334828.
Eritoran 是一种合成脂质 A 拮抗剂，可阻止脂多糖 (LPS) 在细胞表面 MD2-TLR4 受体上结合。LPS 是革兰氏阴性细菌外膜的主要成分，是急性炎症反应的有效激活剂。
确定 TLR4 拮抗剂 Eritoran 是否能显著降低脓毒症引起的死亡率。
设计、地点和参与者：我们在 197 个重症监护病房进行了一项随机、双盲、安慰剂对照、多中心的 3 期临床试验。患者于 2006 年 6 月至 2010 年 9 月入组，最终随访于 2011 年 9 月完成。
患有严重败血症（n=1961）的患者在首发器官功能障碍后 12 小时内按 2:1 的比例随机分组，并接受为期 6 天的 Eritoran 四钠盐（总剂量为 105mg）或安慰剂治疗，分别有 n=1304 和 n=657 名患者接受治疗。
主要终点为 28 天全因死亡率。次要终点为治疗开始后 3、6 和 12 个月的全因死亡率。
两组研究患者的基线特征相似。在改良意向治疗分析（接受至少一剂治疗的随机患者）中，28 天全因死亡率无显著差异，Eritoran 组为 28.1%（366/1304），安慰剂组为 26.9%（177/657）（P=.59；风险比，1.05；95%CI，0.88-1.26；死亡率差异，-1.1；95%CI，-5.3 至 3.1），或 1 年全因死亡率的关键次要终点也无显著差异，Eritoran 组为 44.1%（290/657），安慰剂组为 43.3%（565/1304），1 年死亡时间的 Kaplan-Meier 分析，P=.79（风险比，0.98；0.85-1.13）。在所有预先指定的亚组中均未观察到显著差异。两组间不良事件（包括继发感染率）无差异。
在严重败血症患者中，与安慰剂相比，使用 Eritoran 并未降低 28 天死亡率。
clinicaltrials.gov 标识符：NCT00334828。
