RCT Comparing Reduced-port Robotic and Conventional Laparoscopic Subtotal Gastrectomy

Prospective Multicenter Randomized Controlled Trial Comparing Reduced-Port Robotic and Conventional Laparoscopic Subtotal Gastrectomy for Early Gastric Cancer (REPROG-RCT)

"Study objective The objective of this study is to evaluate whether reduced-port robotic subtotal gastrectomy demonstrates non-inferiority in safety, specifically regarding the incidence of postoperative complications, compared to conventional laparoscopic subtotal gastrectomy in patients with early gastric cancer. Additionally, the study aims to assess differences in efficacy between the two surgical approaches as secondary endpoints.

Study design overview This study is a multicenter, randomized controlled trial involving patients with early gastric cancer. Participants will be randomly assigned in a 1:1 ratio to either the reduced-port robotic surgery group or the conventional laparoscopic surgery group. Outcomes to be observed over a 30-day postoperative period include the incidence of complications, operative time, blood loss, pain levels, length of hospital stay, and quality of life.

Investigational Product/Medical Device Robotic surgical platform Laparoscopic surgical platform Target Sample Size and Rationale The study aims to demonstrate that reduced-port robotic subtotal gastrectomy (experimental group) is non-inferior to conventional laparoscopic subtotal gastrectomy (control group) with respect to the incidence of postoperative complications of grade ≥ 3.

Previous studies have reported that the complication rate for minimally invasive subtotal gastrectomy in early gastric cancer is approximately 4%.

For the non-inferiority test based on comparison of proportions, the following assumptions were used to calculate the required sample size:

• Complication rate in the control group (pC): 4%
• Complication rate in the experimental group (pT): 4%
• Non-inferiority margin (Δ): 5%
• Significance level (α): 2.5% (one-sided)
• Statistical power (1-β): 80%
• Allocation ratio: 1:1
• Expected dropout rate: 10%

Based on these assumptions, the calculated sample size is 242 patients per group. Considering a 10% dropout rate, the adjusted sample size is 269 patients per group, totaling 538 patients for the entire study.Inclusion:

Patients aged 20 to 80 years diagnosed with early gastric cancer (cT1N0) who are eligible for distal subtotal gastrectomy based on endoscopic or imaging findings.

Exclusion:

Presence of distant metastasis Diagnosis of advanced gastric cancer Suspected lymph node metastasis History of previous gastrectomy ASA physical status score > 3 Pregnancy or withdrawal of informed consent Randomization will be performed preoperatively using a web-based system. Surgical procedures will be conducted in accordance with standardized operative guidelines.

Follow-up assessments will be conducted at discharge, on postoperative day 30, and at 3 and 6 months postoperatively.

Endpoints

Primary Endpoint:

Incidence of postoperative complications of Clavien-Dindo grade ≥ III within 30 days after surgery

Secondary Endpoints:

Operative time Estimated blood loss Number of harvested lymph nodes Length of hospital stay Postoperative pain scores Quality of life (including wound-related discomfort and dietary function) Three-year disease-free survival rate Data analysis and statistical Methods Analyses will be conducted on an intention-to-treat (ITT) basis. Categorical variables will be analyzed using the χ² test or Fisher's exact test, as appropriate.

Continuous variables will be analyzed using either the t-test or the Mann-Whitney U test, depending on the distribution of the data.

Survival analyses will be performed using Kaplan-Meier curves and compared with the log-rank test.

Non-inferiority testing will be based on comparisons of 95% confidence intervals.

9. Study Design (Study Groups, Randomization, Blinding, and Study Flow) 9.1 Eligibility Criteria for Participating Surgeons and Standardization and Quality Control of Surgical Procedures Prior to the initiation of this clinical trial, the REPROG-02QC study was conducted to identify and qualify surgeons eligible to participate. Only surgeons approved by the REPROG Committee, based on standardized criteria and assessment of surgical quality, are permitted to participate in this trial. Surgeons' clinical experience and proficiency in surgical techniques are evaluated before being allowed to participate in the randomized controlled trial (RCT). All participating surgeons must apply for participation and obtain approval from their respective Institutional Review Boards (IRBs).

They must also fulfill the following requirement:

Submission and completion of review for three to four unedited cases of reduced-port robotic gastrectomy, which will be evaluated by the committee for adequacy of lymph node dissection, surgical completeness, and intraoperative performance.

In addition, only surgeons affiliated with institutions performing at least 50 gastrectomies per year are eligible to apply for participation in this RCT.

The REPROG Committee will review the submitted videos, assign evaluation scores, and determine whether each surgeon is qualified.

Only surgeons who are officially qualified through this review process will be permitted to participate in the randomization phase of the RCT.

The submitted surgical videos are evaluated by a review committee composed of national and international experts in gastric cancer surgery. The evaluation criteria include adequacy of lymph node dissection, surgical completeness, tissue handling, visualization, and management of intraoperative bleeding. Only those surgeons who meet all the specified surgical evaluation criteria will be permitted to participate in the randomization phase of the trial. Surgeons may be required to undergo re-evaluation or submit additional cases if necessary. This process is designed to ensure quality control of surgical techniques throughout the REPROG study and to secure the internal validity of this multicenter trial.

10.2 Conduct of the Clinical Trial at Participating Institutions and Patient Enrollment The overall coordination and management of this clinical trial will be overseen by the Department of Gastrointestinal Surgery, Severance Hospital, Yonsei University College of Medicine (Coordinating Institution). Surgeons who decide to participate in the trial will receive the necessary documents for IRB submission from the designated study coordinator. Following IRB approval, patient enrollment may begin for those who meet the inclusion criteria. Patient registration and data management will be conducted using a web-based electronic case report form (e-CRF) system provided by Yonsei University Health System.

Patient Enrollment Procedure Eligible patients who meet all inclusion criteria and none of the exclusion criteria will be identified. After receiving a detailed explanation of the study, patients will be asked to sign the informed consent form. Subsequently, eligibility will be reconfirmed through a screening checklist on the web-based randomization system provided by Yonsei University. Upon confirmation, patients will be registered and randomized. The point of randomization coincides with the decision to proceed with surgery and the patient's agreement to participate in the clinical study. Enrollment will be competitive among participating institutions.

Patients will be withdrawn from the study in the following circumstances:

Withdrawal of consent after registration Failure to proceed with surgery within 30 days of registration If more than 30 days have passed, patients must undergo a re-evaluation of eligibility and provide new informed consent to participate in the trial. In the event of erroneous or duplicate registrations identified by individual investigators, the study coordinator must be contacted to correct the records. If identified by the study coordinator, the responsible investigator will be notified to rectify and re-register the patient. (This applies only to subjects in the screening phase before randomization.) The trial will close to enrollment once a total of 538 patients have been randomized and registered.

Randomization Method Randomization will be conducted separately for each participating investigator to ensure a 1:1 allocation ratio. A Baseline Number (BN) will be assigned in the order that patients provide informed consent. Eligible patients will then receive a sequential Allocation Number (AN) according to a pre-generated randomization table. Randomized block design will be used, with each investigator considered a stratification factor. Block sizes will not be disclosed to the investigators to preserve the randomness of allocation. Access to the web-based e-CRF will be secured via issued user IDs and passwords for each participating surgeon. Only authorized users with verified login credentials will be permitted to enter data into the system.

Study Groups

Group A (Conventional Laparoscopy Group):

Subtotal gastrectomy with D1+ lymph node dissection performed via the laparoscopic approach.

Group B (Reduced-Port Robotic Group):

Subtotal gastrectomy with D1+ lymph node dissection performed via the robotic approach using a reduced-port technique (involving three or fewer trocars).

DaVicnci SP robotic system will be used as long as the procedure is performed with three or fewer trocars in a reduced-port configuration that meets the study definition of the experimental group.

Inclusion Criteria:

1. Patients aged between 20 and 80 years diagnosed with early gastric cancer (cT1N0)
2. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
3. Patients with an American Society of Anesthesiologists (ASA) physical status classification of Class I to III
4. Patients with a histologically confirmed diagnosis of gastric adenocarcinoma by endoscopic biopsy prior to surgery
5. Patients with early gastric cancer suspected to have submucosal invasion limited to less than the muscularis propria based on preoperative examinations
6. Patients deemed eligible for distal subtotal gastrectomy based on preoperative assessment
7. Patients who have received a full explanation of the study purpose and procedures, and who voluntarily sign the written informed consent approved by the Institutional Review Board (IRB)

exclusion Criteria:

1. Patients determined to have advanced gastric cancer rather than early gastric cancer based on preoperative endoscopy or computed tomography
2. Patients with confirmed distant metastasis on preoperative examinations
3. Patients with a history of previous gastrectomy
4. Patients with complications from gastric cancer, such as significant obstruction or perforation
5. Patients who have received chemotherapy or radiotherapy for the current gastric cancer diagnosis prior to surgery
6. Patients who have undergone surgery or received chemotherapy or radiotherapy for another primary malignancy within the past 5 years (with the exception of adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix)
7. Vulnerable subjects, including individuals lacking decision-making capacity, pregnant women, or those planning pregnancy
8. Patients who have participated in another clinical trial within the past 6 months or who are currently enrolled in another clinical trial
9. Patients with active synchronous multiple primary malignancies

Exclusion Criteria:

1. Patients determined to have advanced gastric cancer rather than early gastric cancer based on preoperative endoscopy or computed tomography
2. Patients with confirmed distant metastasis on preoperative examinations
3. Patients with a history of previous gastrectomy
4. Patients with complications from gastric cancer, such as significant obstruction or perforation
5. Patients who have received chemotherapy or radiotherapy for the current gastric cancer diagnosis prior to surgery
6. Patients who have undergone surgery or received chemotherapy or radiotherapy for another primary malignancy within the past 5 years (with the exception of adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix)
7. Vulnerable subjects, including individuals lacking decision-making capacity, pregnant women, or those planning pregnancy
8. Patients who have participated in another clinical trial within the past 6 months or who are currently enrolled in another clinical trial
9. Patients with active synchronous multiple primary malignancies