Objective: To evaluate the hemostatic efficacy, safety and immunogenicity of recombinant human thrombin in the treatment of liver wounds that still ooze after conventional surgical hemostasis. Methods: A multicenter, stratified randomized, double-blind, placebo-controlled phase Ⅲ trial with a planned enrollment of 510 subjects at 33 centers, with a 2∶1 randomization to the thrombin group versus the placebo group. An interim analysis will be conducted after approximately 70% of the subjects have completed the observation period. The primary efficacy endpoint was the rate of hemostasis within 6 minutes at the point of bleeding that could be evaluated. Safety analysis was performed one month after surgery, and the positive rates of anti-drug antibody (ADA) and neutralizing antibody were evaluated. Results: At the interim analysis, a total of 348 subjects had been randomized and received the study drug (215 were male and 133 were female). They were aged 19-69 (52.9±10.9)years. Among them, 232 were in the thrombin group and 116 were in the placebo group, with balanced and comparable demographics and baseline characteristics between the two groups. The hemostasis rate at 6 minutes was 71.6% (95%CI:65.75%-77.36%) in the thrombin group and 44.0% (95%CI: 34.93%-53.00%) in the placebo group, respectively (P<0.001). No grade≥3 drug-related adverse events and no drug-related deaths were reported from the study.No recombinant human thrombin-induced immunologically-enhanced ADA or immunologically-induced ADA was detected after topical use in subjects. Conclusion: Recombinant human thrombin has shown significant hemostatic efficacy and good safety in controlling bleeding during liver resection surgery, while also demonstrating low immunogenicity characteristics.
目的： 评价重组人凝血酶对经外科常规止血后依然渗血的肝脏创面的止血疗效、安全性和免疫原性。 方法： 采用多中心、分层随机、双盲、安慰剂对照Ⅲ期试验，计划在33家研究中心入组510例受试者，凝血酶组与安慰剂组为2∶1分层随机分配。在大约70%受试者完成观察后进行期中分析，期中分析结果支持有效则研究提前终止。主要疗效终点为可评价出血点的6 min内止血率。术后1个月进行安全性分析，同时评估抗药物抗体（ADA）及中和抗体的阳性率。 结果： 截止期中分析，共348例受试者接受随机且给予研究药物，其中男215例，女133例，年龄19~69（52.9±10.9）岁，凝血酶组232例，安慰剂组116例，两组基线特征均衡可比。6 min内止血率凝血酶组和安慰剂组分别为71.6%（95%CI：65.75%~77.36%）和44.0%（95%CI：34.93%~53.00%），组间比较差异有统计学意义（P<0.001）。研究中无≥3级药物相关不良事件和药物相关死亡报告。受试者在使用重组人凝血酶后，无免疫增强ADA发生，也无免疫诱导ADA发生。 结论： 重组人凝血酶用于肝脏切除术中创面渗血的止血效果显著，安全性良好，且显示出低免疫原性特征。.