Preventing Ovarian Cancer Through Opportunistic Salpingectomy at the Time of Laparoscopic Cholecystectomy

The investigators will conduct a multi-center, open-label, non-inferiority clinical trial with two sites in British Columbia, Canada, and one site in Ontario, Canada. Recruitment will take place over 30 months from July 1, 2026, to January 31, 2029. Participants will be followed from preoperative assessment until 30 days following discharge from their surgery. The investigators will choose the nearest neighbor match by age at the same site as the intervention patient. The research coordinators (RC) will run each potential eligible control patient by the surgeon running that site to ensure that they would have been eligible for the trial, and their data will be obtained from their electronic medical record. All identifiable data will be removed and replaced with study IDs.

The RC at each site will have access to the electronic booking system at their site and screen eligible patients. They will approach patients and offer them the option to participate in a trial of opportunistic bilateral salpingectomy (OBS) during their laparoscopic cholecystectomy. If patients are interested, they will be provided with an information leaflet which includes a link to an online video, developed for patients, explaining OBS during general surgery. They will be provided with the electronic consent documents by email and offered a paper version should they prefer that option. Should there be any instances where an in-person consenting may not be possible or inconvenient, it will be done over the phone.

The investigators anticipate that 240 OBS patients will be recruited at the end of 30 months, which will ensure sufficient power for the main safety aims. The RC will attend the OR and will collect data on the fallopian tube removal. In the rare instances where the RC is not present, an OR nurse or another person in the OR will perform those duties. The RC will record how long it takes for the surgeon to remove both fallopian tubes. If the patient has had a prior tubal ligation, the surgeon will report that to the RC.

Start time: RC will begin timing fallopian tube removal when the camera and instruments are positioned away from the abdomen and into the pelvis, with or without insertion of additional port sites. The surgeon will signal when fallopian tube removal begins.

End time: The fallopian tube removal will be considered finished when both tubes are separated from the ovaries and uterus. The surgeon will signal when both tubes are separated from the ovaries and uterus, or when the attempt to remove both fallopian tubes was abandoned in cases where OBS was not feasible.

During and after the surgery, the RC will record the following:

1. Blood transfusion or use of hemostatic agents, as measured by any procedure in which whole blood or blood parts are put into a patient's bloodstream through a vein, or any hemostatic agent is used;
2. OR time required to remove fallopian tubes.
3. Total OR time.
4. Clips in place if prior tubal ligation.
5. Number of additional ports placed.
6. Instruments used.
7. Additional instruments that were opened solely for the salpingectomy.

At 30 days after the discharge, the RC would follow up on:

1. Length of hospital stay, as measured from admission time to discharge time;
2. 30-day hospital readmission rate, as indicated by any return to the hospital with an inpatient stay in the 30 days following discharge from their surgery;
3. Surgical site infection, which includes any infection that develops at the site of the surgical incision within 30 days that requires further treatment.

These data are available in the patient's medical chart and are also available through chart review for the patients in the retrospective control group. Perioperative complications will be graded according to the Clavien-Dindo classification of surgical complications, which uses a grading approach. Any Grade 4 or 5 complications will be immediately reviewed by the study team to determine whether the study needs to be stopped.

To determine the cost-effectiveness of OBS at the time of laparoscopic cholecystectomy, the investigators will use the data generated regarding additional OR time and any additional health services considerations, as well as any additional complications, in our modeling. Direct and indirect health care costs will be derived from previously existing sources, including previous publications, and the Canadian Institute for Health Information (CIHI) patient cost estimators, which include provincial cost estimates for laparoscopic cholecystectomy surgeries by province. Lifetime risks of high-grade serous carcinoma (HGSC) will be modeled from the Canadian Cancer Statistics (CCS). Competing mortality risks that are age and sex-dependent will be derived from Canadian Life Tables. The investigators will use published costs for treatment of HGSC5 and compare the direct HGSC-related costs (costs associated with either prevention or treatment of HGSC) across all groups.

Monte Carlo simulations will estimate the number of people who will be diagnosed with HGSC in the future after OBS compared to those not having this procedure, based on the effectiveness data generated from OBS at the time of hysterectomy and tubal sterilization (i.e., risk reduction of 78%). The time horizon will be 50 years. The investigators will allow for uncertainty around various parameters, including the effectiveness of OBS, the proportion of women who will undergo this procedure in the general population, and total health care costs, by conducting extensive sensitivity analyses.

To incorporate measures of quality of life into the model, the investigators will estimate quality-adjusted life years based on utilities associated with various health states, including postoperative recovery and potential complications. The primary outcome measure will be the incremental cost-effectiveness ratio (ICER), and OBS at the time of lap chole surgery will be considered cost-effective if its ICER is less than $50,000 per year of life gained (chosen in accordance with willingness-to-pay research).

Safety Reporting:

There are no clinical risks for patients beyond the standard surgical management for lap chole. Patients will be carefully counselled on the risks, benefits, and alternatives to proceeding with their standard of care operation. All AEs reported spontaneously by the subject or observed by the investigator or their staff will be recorded.

All symptoms that are to be expected according to the surgical procedure and healing process are not considered AEs. All adverse events will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow-up may require additional tests or medical procedures, and/or may require referral to the general physician or a medical specialist.

Perioperative complications will be graded according to the Clavien-Dindo classification of surgical complications, which uses a grading approach. Any Grade 4 or 5 complications will be immediately reviewed by the study team to determine whether the study needs to be stopped. A serious adverse event is any untoward medical occurrence or effect that:

• results in death
• is life-threatening (at the time of the event)
• requires hospitalization or prolongation of existing inpatients' hospitalization
• results in persistent or significant disability or incapacity
• any other important medical event that did not result in any of the outcomes listed above due to medical or surgical intervention but could have been, based upon appropriate judgment by the investigator

Proposed Analyses:

The investigators will calculate the percentage of patients who consented to OBS and went on to successfully have both fallopian tubes removed during their laparoscopic cholecystectomy. Since this is a non-inferiority trial examining whether laparoscopic cholecystectomy with OBS has an adverse event profile that is non-inferior to standard laparoscopic cholecystectomy without OBS, a non-inferiority margin of 5% will be considered clinically meaningful. 95% confidence intervals will be used to describe treatment differences for the safety outcomes and to determine non-inferiority (lower confidence limit ≥5%). The investigators will conduct a per-protocol analysis as the primary population for analysis, given that this is standard for non-inferiority trials; however, the investigators will also complete an intention-to-treat analysis as a secondary analysis. A non-inferiority p-value will be calculated using a Wald test to aid interpretation. Multiple comparison adjustments for the pairwise treatment comparisons will be made:

1. The investigators will conduct a per-protocol analysis as the primary population for analysis, given that this is standard for non-inferiority trials.
2. The investigators will also complete an intention-to-treat analysis as a secondary analysis.

An interim analysis will be conducted annually to evaluate safety and confirm study feasibility by assessing recruitment rates and protocol adherence, and to assess whether any new barriers to the trial are identified.

Data Handling:

A central Research Coordinator located at the Lead Site (Vancouver General Hospital) will be responsible for data handling. All data will be monitored using the University of British Columbia Faculty of Medicine (UBC FoM) REDCap. Quarterly virtual meetings will be conducted with all site leads, RCs, and relevant study personnel. The Principal Investigator will have regular contact with each site lead to ensure enrollment, recruitment, and correct data entry. Patients will be assigned a unique study ID, and no identifiers will be retained for analysis. A master list linking patients' Personal Health Numbers and the study ID will be retained only during data collection to avoid duplication of data entry. The master list will be stored as a password-protected Excel spreadsheet on the institutional share drive (eg, UBC Microsoft OneDrive). Only study personnel will have access to the spreadsheet. Once the collection is completed, this master list will be deleted, and data will be completely de-identified.

All data analyses will be conducted on-site, so that no individual-level data leaves the site. All files will be retained for 5 years after publication. This study will be conducted in accordance with the principles of the Declaration of Helsinki (Brazil, 2013), the guidelines of Good Clinical Practice (GCP) issued by ICH, and the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS 2, 2022).

Each collaborating site is required to obtain ethics approval from its own institutional REB. Summarized study results will be disclosed to participants via email in plain language, along with a copy of the journal article of this study that will be published.