A Study on Comparison of Postoperative Outcome Between Conventional Skin Stapling and Tissue Adhesive (2-octyl Cyanoacrylate) for Skin Closure in Colorectal Cancer
Phase: NA
Conditions: Surgical Site Infection, Colorectal Cancer
Sponsor: Yoon Suk Lee

 
 
Protocol 
 
 
 
 
 
 
Title: Skin Adhesive Glue versus Skin Stapling Comparing 
CLOSure Effectiveness in Colorectal Cancer Surgery 
(CLOSE Trial) 
 
 
Investigational product: 2-octyl cyanoacrylate (Leukoplast® Skin Adhesive, Chemence medical, Inc., USA) 
Protocol number: NCT 06549803 
Study design: A multicenter, non-inferiority, randomized controlled trial with two parallel comparison arms. 
Number of participating centers: 3 centers of tertiary hospitals in South Korea (the Catholic Colorectal group) 
 
 
 
 
STUDY PROTOCOL 
From March 2022  
 
Version 1.0 
 
 
 
 
 

 
1. Background  
Surgical site infection (SSI) represents one of the most common and costly postoperative complications following 
colorectal surgery, with reported incidence rates ranging from 4% to 15% depending on patient and procedural 
factors. SSI prolongs hospitalization, increase healthcare costs, and is associated with reduced patient qulity of 
life. Optimizing skin closure technique is a potentially modifiable determinant of SSI risk.  
Skin stapling devices have long been the standard method for fascial and skin closure in abdominal surgery due 
to their speed, ease of application, and secure wound apposition. However, stapled wounds have been associated 
with greater postoperative pain, visible scarring, the need for subsequent staple removal, and in some series, higher 
SSI rates compared with suture-based alternatives.  
Skin adhesives, including 2-octyl cyanoacrylate formulations (e.g., Leukosan Adhesive), form a flexible, 
watertight microbial barrier within seconds of application, eliminating the need for suture or staple removal and 
potentially reducing pain and improving cosmesis. Retrospective data have suggested that skin adhesive may be 
associated with lower SSI rates and reduced wound care costs compared with skin staples in colorectal procedures. 
However, prospective randomized controlled evidence comparing the two approaches specifically with respect to 
SSI incidence and cost-effectiveness in the laparoscopic colorectal cancer setting is currently absent from the 
literature.  
This trial is designed to address this evidence gap by directly comparing skin adhesive with conventional skin 
stapling in patients undergoing elective laparoscopic or robotic colorectal cancer surgery at three high-volume 
tertiary referral centers.  
 
2. Objectives 
2.1 Primary objective 
To demonstrate the non-inferiority of 2-octyl cyanoacrylate skin adhesive compared with conventional skin 
stapling with respect to the incidence of SSI within 30 days of surgery, assessed at the time of hospital discharge. 
SSI is defined according to Centers for Disease Control and Prevention criteria and includes both superficial 
incisional SSI and deep incisional SSI.  
 
2.2 Secondary objective  
   To compare postoperative pain intensity (VAS score, 0-10) at postoperative days 1 and 3.  
   To compare length of hospital stay.  
   To compare the incidence of major postoperative complications within 30 days 
   To compare total operative times (minutes).  
 To compare total wound-related cost-effectiveness between the two groups, including device cost and wound 
dressing service cost.  
To assess wound healing quality and patient satisfaction via a validated questionnaire administered at the 
outpatient clinic visit one week after discharge.  
 
3. Methods  
3.1 study design  
 This is a prospective, randomized, open-label, multicenter, non-inferiority trial. The trial is reported in 

accordance with the standard protocol items 
3.2. Eligibility Criteria 
3.2.1 Inclusion criteria 
1) Adults patients aged 19-80 years 
2) ASA physical status classification I –III  
3) Histologically confirmed or clinically suspected colorectal adenocarcinoma scheduled for elective curative 
resection by laparoscopic or robotic surgery  
4) Written informed consent provided prior to enrollment  
 
3.2.2 Exclusion criteria  
1) Age over 80 years  
2) Simultaneous resection of ≥2 abdominal organs 
3) Known hypersensitivity to cyanoacrylate compounds 
4) Uncontrolled diabetes mellitus  
5) Emergency surgery  
6) Inability or unwillingness to provide informed consent 
 
3.3 Interventions 
3.3.1. Experimental group – Skin adhesive 
 Following fascial closure, the skin edges are approximately with subcutaneous absorbable sutures and the 
epidermal layer is sealed with 2-octyl cyanoacrylate skin adhesive (Leukosan Adhesive). The adhesive is applied 
in three thin layers with 30 second drying intervals per manufacturer instructions. No additional wound ressing is 
applied.  
3.3.2. Control group- conventional skin stapling  
 Following fascial closure, the subcutaneous layer is sutured by Vicryl and skin is approximately using a 
disposable skin stapler (Visistat Regular). Staples are placed at approximately 5mm intervals. Standard wound 
dressings are applied. Staples are removed at the discretion of the attending surgeon, typically a postoperative day 
7-10.  
 
3.4 Randomization  
Randomization was performed using a computer-generated sequence created by the Department of Biostatistics 
at Seoul St. Mary’s Hospital. Allocation was stratified by surgical approach (laparoscopic vs robotic-assisted) and 
tumor location (colon vs rectum). Within each stratum, block randomization with variable block sizes (4,6, and 8) 
ensured balance while minimizing predictability.  
Allocation concealment was achieved through a centralized, web-based system managed by an independent 
biostatistician not involved in patient recruitment, enrollment, or outcomes assessment. Patients were randomized 

the day before surgery in a 1:1 ratio to either the skin adhesive (Bond) or skin stapling (Stapler) group. Treatment 
allocation was concealed from all clinical staff until assignment.  
 
3.5 Blinding 
This was an open-label trial; patients and clinicians were not blinded. However, outcome assessors were blinded 
to treatment assignment. Physicians performed postoperative wound assessment on the day of discharge, and 
statistical analyses were conducted without knowledge of group assignment until completion. 
The open-label design was necessary duet to the visibly distinct nature of the interventions. To minimize potential 
independent clinical nurse specialists, not involved in surgery or allocation, conducted wound evaluations and 
patient satisfaction surveys.  
 
3.6. Outcomes  
3.6.1 primary Endpoint 
 Incidence of SSI (superficial or deep incisional) within 30 days of surgery.  
3.6.2 Secondary Endpoints  
Outcomes 
Measurement Tool 
Time point  
Pain score 
Visual Analogue Scale (VAS, 0-10) 
POD1, 2, and 3  
Length of hospital stay  
Day from surgery to discharge 
At discharge 
Operative time 
Minutes (skin incision to wound closure) 
Intraoperative  
Major complications 
Clavien-Dindo classification  
Within 30 days 
Cost effectiveness 
Dressing supply cost, dressing service 
cost, Dressing frequency 
Until discharge 
Patient satisfaction and wound 
quality  
Validated 
wound 
questionnaire, 
investigator wound assessment 
1 week postop discharge OPD 
visit  
 
3.7. Data Collection  
Baseline variables will be collected preoperatively and include: age, sex, body mass index (BMI), ASA class, 
diabetes mellitus status, smoking history, prior abdominal surgery, preoperative serum white blood cell count 
(WBC), and C-reactive protein (CRP). Intraoperative data will include operative technique, type of resection, 
specimen extraction incision length, operative time, and estimated blood loss. Postoperative data will include 
histopathological results (tumor type, TNM stage), SSI occurrence, VAS pain scores, length of stay, complications, 
wound care resource utilization, and patient-reported satisfaction.  
All data will be recorded on standardized case report forms (CRFs) and entered into a password-protected 
electronic database. Source data verification will be performed quarterly by the principle investigator.  
 
3.8 Sample size calculation  
 Sample size was calculated in consultation with the department of Biostatics, Seoul St. Mary’s Hospital. The 
reference SSI rate following skin stapling in laparoscopic colorectal surgery was estimated at 5.8%, based on 
published literature (Lee CS et al, 2020). The non-inferiority margin was set at 0.99 percentage points (i.e., the 
absolute difference in SSI rate between the skin adhesive and stapling groups must not exceed 0.99% in favor of 
stapling for the tissue adhesive to be declared non-inferior).  

Using a one-sided Z test (unpooled), one-sided alpha of 0.025, and power of 80%, the required sample size is 152 
participants per group, for a total of 304 participants. No adjustment for anticipated dropout has been made 
because both interventions are applied at the time of surgery; however, a 10% safety margin may be considered 
at the interim review.  
 
Analysis of Non-Inferiority Tests of Two Independent Proportions 
 
Numeric Results for Non-Inferiority Tests Based on the Difference: P1 - P2 
H0: P1 - P2 ≥ D0.   H1: P1 - P2 = D1 < D0.   Test Statistic: Z test (unpooled) 
 
Target 
Actual 
 
 
 
Ref. 
P1|H0 
P1|H1 
NI 
Diff 
Diff 
Target 
Power 
Power 
N1 
N2 
N 
P2 
P1.0 
P1.1 
D0 
D1 
Alpha 
 
0.80 
0.80233 
152 
152 
304 
0.0580 
0.0679 
0.0100 
0.0099 
-
0.0480 
0.0250 
 
 
Note: Direct Binomial distribution calculations for alpha and power were only used when both N1 and N2 were 
less 
than 100. In all other cases, Normal approximation was used. 
 
Report Definitions 
Target Power is the desired power value (or values) entered in the procedure. Power is the probability of 
   rejecting a false null hypothesis. 
Actual Power is the power obtained in this scenario. Because N1 and N2 are discrete, this value is often 
   (slightly) larger than the target power. 
N1 and N2 are the number of items sampled from each population. 
N is the total sample size, N1 + N2. 
P2 is the proportion for Group 2. This is the standard, reference, or control group. 
P1 is the treatment or experimental group proportion. P1.0 is the largest treatment-group response rate that 
   still yields a non-inferiority conclusion. P1.1 is the proportion for Group 1 at which power and sample 
   size calculations are made. 
D0 is the non-inferiority margin. It is the difference P1 - P2 assuming H0. D1 is the difference P1 - P2 
   assumed for power and sample size calcualtions. 
Target Alpha is the input probability of rejecting a true null hypothesis. Actual Alpha is the value of alpha 
   that is actually achieved. 
 
Summary Statements 
Sample sizes of 152 in group one and 152 in group two achieve 80% power to detect a 
non-inferiority margin difference between the group proportions of 0.0099. The reference group 
proportion is 0.0580. The treatment group proportion is assumed to be 0.0679 under the null 
hypothesis of inferiority. The power was computed for the case when the actual treatment group 
proportion is 0.0100. The test statistic used is the one-sided Z test (unpooled). The 
significance level of the test was targeted at 0.0250.  
 
 
3.9 Statistical Analysis  
All analyses will be performed using SPSS version 27.0 (IBM Corp) or R version 4.3 or later. The primary non-
inferiority analysis will be conducted on both the per-protocol (PP) population and the intention-to-treat (ITT) 
population; non-inferiority will be claimed only if both analyses are concordant.  
The primary endpoint (SSI rate) will be analyzed using a one-sided Z test for the difference in proportions, with 
the 95% confidence interval for the difference (skin adhesive minus stapling) reported. Non-inferiority will be 
concluded if the upper bound of the 95% confidence interval is below the pre-specified non-inferiority margin of 
0.99 percentage points.  

Continuous secondary endpoints (VAS, length of stay, operative time, cost) will be compared using the Student’s 
t-test or Mann-Whitney U test as appropriate. Categorical variables (complication rates, patient satisfaction 
categories, pathological stage) will be analyzed using the chi-square test or Fisher’s exact test. A two-tailed p-
value of <0.05 will be considered statistically significant for all secondary comparisons.  
 
4. Study Schedule 
 
 
 
 
Study Period 
 
 
Enrollment 
Allocation 
Post-allocation  
Close-out 
  
Time point 
-2 to 0 day 
Operation 
day  
Postoperativ
e day 1 
Postoperati
ve day 2 
Postoperati
ve day 3 
Discharge 
First OPD 
f/u 
Enrollment 
Eligibility screen  
O 
 
 
 
 
 
 
Informed 
consent  
O 
 
 
 
 
 
 
Randomization   
 
O 
 
 
 
 
 
Allocation  
 
O 
 
 
 
 
 
Intervention 
Experimental 
intervention 
 
O 
 
 
 
 
 
Control 
intervention  
 
O 
 
 
 
 
 
Assessment 
Demographical 
data 
O 
 
 
 
 
 
 
Medical history 
O 
 
 
 
 
 
 
Laboratory  
O 
O 
 
O 
 
O 
 
Parameters of 
surgical 
procedure 
 
O 
 
 
 
 
 
VAS score 
 
O 
O 
O 
O 
 
 
Documentation 
of SSI 
 
O 
O 
O 
O 
 
O 
Documentation 
of other 
complication 
 
O 
O 
O 
O 
 
O 
Length of 
hospital stay 
 
 
 
 
 
 
O 
readmission 
 
 
 
 
 
 
O 
Patient 
questionnaire 
 
 
 
 
 
 
O 
Pathologic 
results 
 
 
 
 
 
 
O 
Cost outcomes 
 
 
 
 
 
 
O 
 
 
5. Safety considerations 
5.1 Anticipated Adverse Events 
Both study interventions represent standard of care wound closure modalities routinely used in clinical practice. 
No additional risk is introduced beyond routine postoperative wound complications. Anticipated adverse events 
include:  
 
Wound dehiscence 

 
SSI (Superficial or deep incisional) 
 
Allergic or contact dermatitis (potential for tissue adhesive group) 
 
Staple-site pain or hypersensitivity (skin stapling group) 
 
5.2 Stopping Rules and Withdrawal Criteria 
 An individual participant will be withdrawn from the study if:  
 
The participant withdraws consent at any time 
 
The participant receives wound-healing-modifying medications (immune-suppressants or systemic 
corticosteroids) not present at baseline 
 
The participant undergoes an unplanned additional abdominal surgery within the observation period 
There are no predefined stopping rules for the overall trial, as both interventions carry minimal incremental risk 
beyond standard care.  
 
5.3. Adverse Event Reporting  
All adverse events will be recorded from the time of randomization through the 30-day follow-up visit. Serious 
adverse events (SAEs) will be reported to the IRB within 24 hours of the investigator’s awareness and managed 
according to institutional and national regulatory guidelines.  
 
Reference  
1. Lee CS, Han SR, Kye BH, et al. Surgical skin adhesive bond is safe and feasible wound closure method to 
reduce surgical site infection following minimally invasive colorectal cancer surgery. Ann Surg Treat Res. 
2020;99(3):146-152. doi:10.4174/astr.2020.99.3.146 
2. Allegranzi B, Bischoff P, de Jonge S, et al. New WHO recommendations on preoperative measures for 
surgical site infection prevention: an evidence-based global perspective. Lancet Infect Dis. 2016;16(12):e276-
e287. doi:10.1016/S1473-3099(16)30398-X 
3. Merkow RP, Ju MH, Chung JW, et al. Underlying reasons associated with hospital readmission following 
surgery in the United States. JAMA - J Am Med Assoc. 2015;313(5):483-495. doi:10.1001/jama.2014.18614 
4. Clay FSH, Walsh CA, Walsh SR. Staples vs subcuticular sutures for skin closure at cesarean delivery: A 
metaanalysis of randomized controlled trials. Am J Obstet Gynecol. 2011;204(5):378-383. 
doi:10.1016/j.ajog.2010.11.018 
5. Kwon JY, Yun HG, Park IY. N-Butyl-2-cyanoacrylate tissue adhesive (Histoacryl) vs. subcuticular sutures 
for skin closure of Pfannenstiel incisions following cesarean delivery. PLoS One. 2018;13(9). 
doi:10.1371/journal.pone.0202074