Health Ricerca e Sviluppo, Global Contractor for STOPSHOCK National Plan of Military Research Ministry of Defence, Rome, 00187, Italy.
Department of Medicine and Division of Clinical Pharmacology, School of Medicine, UNIMORE, Policlinico, Modena, 41124, Italy.
Mil Med Res. 2024 Aug 19;11(1):56. doi: 10.1186/s40779-024-00555-2.
Undifferentiated shock is recognized as a criticality state that is transitional in immune-mediated topology for casual risk of lethal microcirculatory dysfunction. This was a sensitivity analysis of a drug (tetracosactide; TCS10) targeting melanocortin receptors (MCRs) in a phase 3 randomized controlled trial to improve cardiovascular surgical rescue outcome by reversing mortality and hemostatic disorders.
Sensitivity analysis was based on a randomized, two-arm, multicenter, double-blind, controlled trial. The Naïve Bayes classifier was performed by density-based sensitivity index for principal strata as proportional hazard model of 30-day surgical risk mortality according to European System for Cardiac Operative Risk Evaluation inputs-outputs in 100 consecutive cases (from August to September 2013 from Emilia Romagna region, Italy). Patients included an agent-based TCS10 group (10 mg, single intravenous bolus before surgery; n = 56) and control group (n = 44) and the association with cytokines, lactate, and bleeding-blood transfusion episodes with the prior-risk log-odds for mortality rate in time-to-event was analyzed.
Thirty-day mortality was significantly improved in the TCS10 group vs. control group (0 vs. 8 deaths, P < 0.0001). Baseline levels of interleukin (IL)-6, IL-10, and lactate were associated with bleeding episodes, independent of TCS10 treatment [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.39-2.79; OR = 1.53, 95%CI 1.17-2.12; and OR = 2.92, 95%CI 1.40-6.66, respectively], while baseline level of Fms-like tyrosine kinase 3 ligand (Flt3L) was associated with lower bleeding rates in TCS10-treated patients (OR = 0.31, 95%CI 0.11-0.90, P = 0.03). For every 8 TCS10-treated patients, 1 bleeding case was avoided. Blood transfusion episodes were significantly reduced in the TCS10 group compared to the control group (OR = 0.32, 95%CI 0.14-0.73, P = 0.01). For every 4 TCS10-treated patients, 1 transfusion case was avoided.
Sensitivity index underlines the quality target product profile of TCS10 in the runway of emergency casualty care. To introduce the technology readiness level in real-life critically ill patients, further large-scale studies are required.
European Union Drug Regulating Authorities Clinical Trials Database (EudraCT Number: 2007-006445-41 ).
未分化性休克被认为是一种临界状态，在免疫介导的拓扑结构中具有过渡性，是偶然发生致命性微循环功能障碍的风险因素。这是一项针对黑素皮质素受体（MCR）的药物（四氢皮质素；TCS10）的 3 期随机对照试验的敏感性分析，该试验旨在通过逆转死亡率和止血障碍来改善心血管外科抢救结果。
敏感性分析基于一项随机、双盲、对照的两臂、多中心试验。在 100 例连续病例（2013 年 8 月至 9 月，来自意大利艾米利亚-罗马涅地区）中，根据欧洲心脏手术风险评估输入-输出，采用基于密度的敏感指数对主要层进行朴素贝叶斯分类器分析，以确定 30 天手术风险死亡率的比例风险模型。患者包括基于代理的 TCS10 组（10mg，手术前单次静脉推注；n=56）和对照组（n=44），并分析细胞因子、乳酸和出血-输血事件与死亡率的先前风险对数比值与时间事件的关系。
与对照组相比，TCS10 组的 30 天死亡率显著降低（0 例死亡与 8 例死亡，P<0.0001）。白细胞介素（IL）-6、IL-10 和乳酸的基线水平与出血事件相关，独立于 TCS10 治疗[比值比（OR）=1.90，95%置信区间（CI）1.39-2.79；OR=1.53，95%CI 1.17-2.12；OR=2.92，95%CI 1.40-6.66，分别]，而 Fms 样酪氨酸激酶 3 配体（Flt3L）的基线水平与 TCS10 治疗患者较低的出血率相关（OR=0.31，95%CI 0.11-0.90，P=0.03）。每治疗 8 例 TCS10 患者，就可避免 1 例出血。与对照组相比，TCS10 组的输血事件显著减少（OR=0.32，95%CI 0.14-0.73，P=0.01）。每治疗 4 例 TCS10 患者，就可避免 1 例输血。
敏感性指数强调了 TCS10 在紧急事故护理跑道上的优质目标产品特性。为了在重症患者中引入技术就绪水平，还需要进一步的大规模研究。
欧洲药品管理局临床试验数据库（EudraCT 编号：2007-006445-41）。
