Medical-Surgical ICU Department and Inserm CIC1435 & UMR1092, CRICS-TRIGGERSEP Network, CHU Limoges, Limoges, France.
Department of Critical Care Medicine, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.
Intensive Care Med. 2020 Jul;46(7):1425-1437. doi: 10.1007/s00134-020-06109-z. Epub 2020 May 28.
Nangibotide is a specific TREM-1 inhibitor that tempered deleterious host-pathogens interactions, restored vascular function, and improved survival, in animal septic shock models. This study evaluated the safety and pharmacokinetics of nangibotide and its effects on clinical and pharmacodynamic parameters in septic shock patients.
This was a multicenter randomized, double-blind, two-stage study. Patients received either continuous infusion of nangibotide (0.3, 1.0, or 3.0 mg/kg/h) or placebo. Treatment began < 24 h after shock onset and continued for up to 5 days. Safety primary outcomes were adverse events (AEs), whether serious or not, and death. Exploratory endpoints evaluated nangibotide effects on pharmacodynamics, organ function, and mortality, and were analyzed according to baseline sTREM-1 concentrations.
Forty-nine patients were randomized. All treatment emergent AEs (TEAEs) were collected until Day 28. No significant differences were observed in TEAEs between treatment groups. No drug withdrawal linked to TEAE nor appearance of anti-drug antibodies were reported. Nangibotide pharmacokinetics appeared to be dose-proportional and clearance was dose-independent. Nangibotide did not significantly affect pharmacodynamic markers. Decrease in SOFA score LS mean change (± SE) from baseline to Day 5 in pooled nangibotide groups versus placebo was - 0.7 (± 0.85) in the randomized population and - 1.5 (± 1.12) in patients with high baseline plasma sTREM-1 concentrations (non-significant). This pattern was similar to organ support end points.
No significant increases in TEAEs were detected in nangibotide-treated patients versus placebo. These results encourage further evaluation of nangibotide and further exploration of plasma sTREM-1 concentrations as a predictive efficacy biomarker.
Nangibotide 是一种特定的 TREM-1 抑制剂，可调节有害的宿主-病原体相互作用，恢复血管功能，提高动物感染性休克模型的存活率。本研究评估了 nangibotide 的安全性和药代动力学特性，以及其对感染性休克患者临床和药效学参数的影响。
这是一项多中心、随机、双盲、两阶段研究。患者接受持续输注 nangibotide（0.3、1.0 或 3.0mg/kg/h）或安慰剂。治疗在休克发作后<24 小时开始，并持续 5 天。安全性主要结局为不良事件（AE），无论是否严重，以及死亡。探索性终点评估了 nangibotide 对药效学、器官功能和死亡率的影响，并根据基线 sTREM-1 浓度进行了分析。
49 名患者被随机分组。所有治疗期间出现的不良事件（TEAE）均被收集至第 28 天。各组间治疗期间出现的不良事件（TEAE）无显著差异。未报告因 TEAE 停药或出现抗药物抗体的情况。nangibotide 的药代动力学似乎呈剂量比例关系，清除率与剂量无关。nangibotide 未显著影响药效学标志物。与安慰剂相比，pooled nangibotide 组从基线到第 5 天 SOFA 评分 LS 均值变化（±SE）在随机人群中为-0.7（±0.85），在基线血浆 sTREM-1 浓度较高的患者中为-1.5（±1.12）（无显著差异）。这种模式与器官支持终点相似。
与安慰剂相比，nangibotide 治疗患者的 TEAEs 无显著增加。这些结果鼓励进一步评估 nangibotide，并进一步探索血浆 sTREM-1 浓度作为预测疗效的生物标志物。
