Initially, eight sites of secondary or tertiary hospitals in South Korea have begun this trial. All participating investigators have been adequately trained and prepared according to the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use – good clinical practice (GCP) rules for taking part in this trial. This trial is still open for recruitment at participating centers.
Trial population and eligibility
All gastrointestinal surgical patients undergoing open abdominal surgery, either elective or emergent, will be screened for eligibility. Patients who satisfy the following criteria will be included: 1) patients must be in between the ages of 18 to 75; 2) open laparotomy; and 3) surgery for stomach, small intestine, or colon and rectum. Patients with any of the following will be excluded: 1) presence of concurrent infection in the abdominal wall; 2) open conversion from laparoscopic surgery; 3) presence of poor nutritional status indicated by a nutrition risk screening (NRS) 2002 score greater than 3; 4) patients undergoing combined hepatobiliary surgery; 5) pregnant or breast-feeding women; 6) moderate to severe immunosuppression state, defined as previous organ or bone marrow transplantation, concurrent steroid administration (more than 10 mg prednisolone daily or an equivalent dose of any other steroid), or concurrent administration of other immunosuppressive or chemotherapeutic agents within the last 2 weeks prior to trial intervention. Once an investigator explains the extent and nature of the COVER trial to an eligible patient, informed consent will be obtained.
A total of 434 patients will be analyzed, considering an estimated dropout rate of approximately 5%. A total of 458 patients will be recruited, and 229 patients will be randomly assigned to each group. The trial flow is outlined in Figure 1.
This clinical trial is a prospective, multicentered, patient-blinded, randomized controlled trial with two parallel comparison arms.
Recruitment and trial timeline
The eight centers of secondary or tertiary hospitals in South Korea have been actively conducting the trial since June 2017. Since then, 4 other centers have joined the trial recruitment, and this trial is still open for recruiting participating centers. All investigators, physicians or nurses are required to complete the ICH-GCP training course. Patients will be recruited for approximately 48 months. The last follow-up will be taken at 30 days after the last recruited patient undergoes the trial intervention. The SPIRIT figure shows the study schedule of enrollment, interventions and assessments (Fig. 2). A SPIRIT checklist is available in Additional file 1. An interim analysis is planned when 50% of the enrollment is reached. Depending on the results of the interim analysis, the subsequent research process and timeline can be modified.
Randomization and blinding
Stratification will be performed according to the participating center and the type of wound classification. The wound types will be divided into two groups: one with clean or clean-contaminated and the other with contaminated or dirty, infected. A web-based patient registry (http://cover.e-trial.co.kr) will be applied to generate the allocation sequence just before the beginning of the operation, providing adequate concealment for the allocation sequence. The group allocation and randomization number will be predefined by a biostatistician of the Catholic Medical Center in Seoul, South Korea. To assure balanced group size in the course of the accrual, a permuted block randomization with the size of 2 or 4 is applied. Participating surgeons cannot be blinded to allocated treatment. However, the patient will be blinded for the trial intervention since they are under general anesthesia once the operation starts. The data manager will also be blinded because there is no direct access to either the trial intervention or the randomization.
Preoperative bowel preparation, type of skin preparation and drape, the use of perioperative antibiotics, and the details of the surgical procedure will follow the policy of an individual surgeon in each center. The experimental arm will be provided with a circular polyethylene drape (O Trac®, Asung Medical Inc. South Korea) to cover the incision site in the abdomen. It is a double-ring type of sterile, cylindrical wound protector consisting of inner and outer rings with a polyethylene sheath. The wound protector is left in situ throughout the operation and is removed just before closing the abdominal wall. The method of wound closure and insertion of wound drainage will also follow the policy of an individual surgeon in each center.
For the control arm, conventional surgical dressing gauze will be used to protect the incision site during the surgical procedure. There are no differences in surgical technique, other devices, or the environment.
No additional risks to the study patients are expected. The circular polyethylene wound protector has established clinical safety and has been already in clinical applications with the approval of the Korean Medical Device Information and Technology Assistance Center, MDITAC. None of the technical details other than wound protection are affected by the trial.
The primary end point of the COVER trial is the rate of SSI, defined by the diagnostic criteria suggested by the Center for Disease Control (CDC) within 30 days after surgery . The postoperative wound condition will be evaluated at postoperative weeks 1, 2, and 4. The secondary end points include the length of postoperative hospital stay, the re-admission rate, and the rate of surgical complication other than SSI. The incidence of 30-day postoperative complications will be stratified according to the modified Clavien-Dindo Classification .
Data management and monitoring
All required information will be recorded through an electronic case reporting form (eCRF) on the web-based patient registry by the investigator or a designated representative. Baseline characteristics, including age, sex, body mass index, American Society of Anesthesiologists score, history of smoking and alcohol consumption, history of previous chemotherapy, radiotherapy, abdominal surgery, steroid or immunosuppressive drug use, history of diabetes or malignancies in the gastrointestinal tract and nutritional status based on the NRS 2002 score will be collected. Laboratory parameters (white blood cell count and c-reactive protein and albumin levels) will be collected preoperatively, on the operation day and on postoperative day 2, if available. The parameters for surgical procedure, including operation type (emergent or elective), site of operation (stomach, small intestine or large intestine), level of wound contamination according to CDC classification, method of skin preparation, antibiotics use, operation time, bowel anastomosis and stoma formation, skin closure material, length of skin incision, draining tube for the wound and body temperature during the operative procedure, will be collected. Postoperatively, the surgical wound will be evaluated at postoperative weeks 1, 2, and 4. A photograph of the wound at each office visit will be taken and documented, if agreed. If SSI is detected, the classification and the postoperative date of diagnosis will be recorded. Bacterial culture of the infected wound will be performed. Postoperative complications according to the modified Clavien-Dindo classification, postoperative length of hospital stay and re-admission will be noted. An investigator or research coordinator at each center will enter the data using the eCRF. The principle investigator is responsible for data completeness and the accuracy of the documentation. At the end of the trial, the study data and personal information of the enrolled patients will be archived for 3 years.
The trial data will be monitored by an independent institution experienced in the monitoring of clinical trials (Medical Excellence, Inc.) in Seoul, Korea. Monitoring will be performed in accordance with ICH-GCP guidelines .
Safety evaluation and reporting of adverse events
All adverse events or serious adverse events, occurring from the moment of randomization until the end of the 30-day follow-up, will be recorded and reported by the investigators.
Sample size calculation
The sample size calculation is based on the primary end point of surgical site infections within 30 days after the index operation. Previous reports on the incidence of SSI have indicated that the rate of SSI may vary depending on the wound classification, the procedure, the surveillance criteria, and the quality of data collection . The incidence of SSI for clean-contaminated wounds has been reported to be as high as 10% . For contaminated wounds, the incidence was approximately 25% [11,7]. For dirty, infected wounds, the incidence may reach up to 40% [5-7]. In this trial, the ratio of operations with clean-contaminated, contaminated, and dirty, infected wound is assumed to be 20:40:40; therefore, the expected incidence of SSI for the control group is 28%. For the experimental group, the incidence of SSI will be decreased by 40%. Thus, the rate of SSI in the experimental group will be approximately 17%. The sample size is determined to achieve a study power of 80%, with 95% 2-sided confidence limits. The actual sample size amounts to 434 participants. However, considering a dropout rate of up to 5%, a total of 458 patients, 229 patients in each group, will be enrolled in this study.