Recombinant human thrombin (Zelgen Biopharma)

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.

Topical hemostatic agents can be classified as active or passive. This study compared the hemostatic efficacy of an active agent, recombinant thrombin (RECOTHROM^® [rT]) plus gelatin sponge carrier versus a passive agent, oxidized regenerated cellulose (TABOTAMP^®/SURGICEL^® [ORC]), in a porcine liver abrasion model.

Eight pigs were used, four of them were heparinized. A total of 80 liver lesions were created, 40 of them in heparinized pigs. Lesions were treated with rT plus gelatin sponge or ORC. Bleeding rate was quantified before treatment by applying pre-weighed gauze. Time to hemostasis was assessed visually for 10 minutes.

Seven of the 80 lesions were excluded for having initial bleeding rates exceeding the target of 10 g/min. Sixteen and 20 lesions were treated with rT plus gelatin sponge and 19 and 18 lesions were treated with ORC, in non-heparinized and heparinized animals, respectively. Time to hemostasis (median [IQR]) was significantly shorter with rT plus gelatin sponge (30 [30,30] seconds) in heparinized and non-heparinized animals versus ORC in non-heparinized (180 [120,210] seconds) and heparinized animals (215 [135,345] seconds); P < 0.0001 for both comparisons. In heparinized animals, ORC took longer to achieve hemostasis, with treatment failure in 2/18 lesions. Time to hemostasis with ORC was longer for lesions in heparinized animals with initial bleeding rates of >5-10 g/min (285 [225,394] seconds) versus ≤5 g/min (175 [108,290] seconds).

In this model, rT plus gelatin sponge carrier (active) was a more effective hemostat than ORC (passive) in both heparinized and non-heparinized animals.