Effect of Thrombin-containing Collagen-based Hemostatic Matrix

1. Synopsis

- Title: Randomized controlled Study to evaluate the Effect of Thrombin-containing Collagen-based Hemostatic Matrix on Prevention of Pancreatic fistula after Pancreatectomy

- Study center: Single center from Korea

- Study type: Single center prospective randomized controlled study

- Planned study dates: February 2018 to September 2020

2. Objectives

■ The aim of this study was to evaluate the safety and efficacy of flowable thrombin containing collagen hemostat matrix (T-C matrix) over the thrombin coated L-dopa contained collagen patch (T-CD patch) on clinical outcomes including PPH and POPF as a randomized controlled clinical trial.

3. Background

- Hemostasis is the most basic and important procedure as a treatment for bleeding that inevitably follows most surgical procedures. Recently, with the development of pancreatic surgery and postoperative management, the mortality rate associated with surgery has decreased significantly, but the rate of complications due to massive bleeding or leakage of pancreatic fluid during surgery has not changed significantly. In hepatobiliary and pancreas (HBP) surgery, post-pancreatectomy hemorrhage (PPH) and postoperative pancreatic fistula (POPF) are both the main source of major morbidity and mortality.

- Collagen is a natural substrate for various kinds of animal cells, and contains a relatively large amount compared to other proteins in animal tissues, and can be easily extracted and purified from animal tissues. Collagen not only has low antigenicity, but also has excellent hemostatic effect and cell attachment ability, so it is often used as a major component of hemostatic agents and artificial tissue substitutes. In addition, collagen provides an environment in which fibroblasts can be produced and induces wound healing by inactivating elastase and matrix metalloproteases (MMPs).

- The investigators developed a novel flowable thrombin containing collagen hemostat matrix (T-C matrix) having flowable paste-like form. The T-C matrix consists of two connectable syringes, one of which contains collagen granules and thrombin, and the other contains calcium chloride (CaCl2) solution. Due to the flowable characteristic of the resultant matrix, T-C matrix can be easily applicable to irregular surface such as surgical site where anastomotic leakage is a concern. Currently, thrombin /coated L-3,4-dihydroxyphenylalanine (L-dopa DOPA) contained collagen patch (T-CD patch) are using on prevention of leakage and bleeding in pancreatic surgery. Although L-DOPA is known to contribute to adhesiveness which facilitates application of T-CD patch on wound sites, there are some controversial studies that L-DOPA have cytotoxicity and may induce inflammatory reaction with a high dose.

4. Methodology

- The clinical study was designed to evaluate the effect of T-C matrix on the prevention of leakage in a pancreatectomy. The expected number of participants is 60.

- This clinical study is a randomized prospective comparative study of the outcome according to the hemostat materials as a non-inferiority test, and the research hypothesis is as follows.

√ Null Hypothesis: There is no difference in the incidence of POPF between patients who were applied TC matrix (CollaStat®, Dalim Tissen. Co., Ltd., Korea) and T-CD patch (CollaSeal®, Dalim Tissen Co. Ltd., Korea) after pancreatectomy.

- In the case of evaluating the incidence of POPF after pancreatectomy, the results of previous studies of the 'leakage' ratio showed a leak prevention effect (θA) = 88% of the existing treatment method of CollaSeal® analog (Montorsi M et al. 2012). The new treatment effect (θT) is intended to demonstrate non-inferiority that does not exceed the non-inferiority limit (δ) compared to the existing treatment effect (θA). The non-inferiority limit (δ) was calculated by more than 75% of the existing treatment effect. The non-inferiority limit was calculated to be 0.22 based on the case where more than 75% of the 88% of the existing treatment method is confirmed, that is, the treatment success rate is more than 66%. It was decided that CollaStat® was non-inferior to CollaSeal® when the lower limit of the 95% CI for the difference between the two groups was greater than -0.22. If the allocation ratio between the two groups is 1: 1 and the first-class error α = 5% and the second-class error β = 20%, considering the dropout rate of 10%, 30 study groups and control groups each need 30 subjects.

- The random assignment of this study is assigned according to the order of assignment in the planning stage of the study as a block randomization scheme with appropriate block size set.