Loose Seton Prior to Surgery for Single-tract Cryptoglandular Fistula vs no Seton (SETON)

Cryptoglandular anal fistulas are a burdensome and often recurrent condition that can substantially affect quality of life and lead to prolonged treatment trajectories. In patients with a single-tract mid-high or high cryptoglandular anal fistula, treatment is commonly aimed at closure of the fistula while preserving continence. In current practice, many patients first undergo placement of a loose seton before definitive sphincter-preserving surgery. This staged approach is widely used in daily practice, but high-quality evidence supporting a benefit of routine preoperative seton placement is limited. Retrospective data suggest that preoperative seton drainage may not clearly improve outcomes before definitive repair. Because seton placement adds an additional procedure, may prolong treatment, and may increase patient burden and healthcare costs, a randomized trial is needed to determine whether this step can be safely omitted.

The SETON trial is a multicentre, randomized, controlled, non-inferiority trial with an integrated cost-utility analysis. The trial compares two accepted treatment strategies for patients with a single-tract non-purulent mid-high or high cryptoglandular anal fistula. In the intervention group, participants undergo loose seton placement using a non-cutting silicone vessel loop, followed by definitive sphincter-preserving surgery after approximately 8 weeks. In the comparator group, participants proceed directly to definitive sphincter-preserving surgery without prior seton placement. The definitive sphincter-preserving procedure is selected by the treating surgeon according to local practice and anatomical characteristics of the fistula and may include advancement flap (MAF), ligation of the intersphincteric fistula tract (LIFT), or laser ablation of the fistula tract (LAFT). The planned treatment method is recorded before randomization and used as a stratification factor.

Eligible participants are adults aged 18 years or older with a single-tract non-purulent mid-high or high cryptoglandular anal fistula. Key exclusion criteria are anorectal abscess, multiple or complex anorectal fistulas, inflammatory bowel disease or clinical suspicion requiring further investigation, history of anorectal malignancy, immunosuppressive medication use at the time of surgery, history of pelvic radiation, and pregnancy or lactation. Participants must also be able to complete Dutch-language questionnaires sent by email.

After written informed consent and baseline data collection, participants are randomized in a 1:1 ratio through the secure web-based Castor EDC system. Randomization is stratified by participating centre and by planned sphincter-preserving treatment method to promote balance between treatment arms. Because the two treatment pathways are visibly different, the trial is unblinded for participants and treating surgeons. Consecutive eligible patients are recruited at participating Dutch centres. Trial participation adds limited burden beyond standard care, mainly informed consent and follow-up assessments.

The primary outcome is successful fistula closure at 26 weeks after final surgery. Fistula closure is defined as absence of an external opening or discharge on physical examination and is confirmed by MRI or endoanal ultrasound when clinical uncertainty remains. Secondary outcomes include postoperative complications, need for re-intervention, pain intensity, time to return to work, continence assessed with the Vaizey score, fistula-related quality of life assessed with the FIQL, generic quality of life assessed with the EQ-5D-5L, patient-reported anorectal symptoms measured with proctoPROM, and healthcare and societal costs. Outcomes are reported in line with the Anal Fistula Core Outcome Set.

Participant-reported outcomes are assessed at prespecified time points. EQ-5D-5L and proctoPROM are completed at baseline, 1 week, 6 weeks, 6 months, and 12 months. Vaizey/FIQL are completed at baseline, 6 weeks, 6 months, and 12 months. The iPCQ and iMCQ are completed at 6 and 12 months, according to the current schedule table in the protocol. Clinical outcomes, including healing, complications, re-interventions, and resource use, are collected from patient records and case report forms. Data are entered into Castor EDC using coded participant identifiers, and the code key is maintained locally in the investigator site file. Study data are retained for 15 years in accordance with applicable Dutch and European requirements.

The sample size calculation is based on a non-inferiority comparison for fistula closure. Assuming an expected healing rate of 60% with standard care, a non-inferiority margin of 15 percentage points, 80% power, and a 5% significance level, 126 participants per group are required. Allowing for 10% loss to follow-up, the total required sample size is 277 participants. Data will be analyzed according to both the intention-to-treat and per-protocol principles, with the per-protocol analysis leading for the non-inferiority conclusion. The primary analysis compares the difference in healing proportions between groups with corresponding 95% confidence intervals. Non-inferiority will be concluded if the lower bound of the 95% confidence interval remains above the prespecified non-inferiority margin of -15 percentage points. Secondary continuous outcomes will be analyzed using t-tests or Mann-Whitney U tests as appropriate, categorical outcomes using chi-square or Fisher's exact tests, and repeated questionnaire outcomes using linear mixed models. Missing data will be handled using multiple imputation with predictive mean matching when prespecified conditions are met. No interim analysis is planned.

The trial also includes an economic evaluation. Cost-effectiveness analysis will estimate cost per successfully healed fistula, and cost-utility analysis will estimate cost per quality-adjusted life year (QALY). Both analyses will be conducted from a societal perspective over a 12-month time horizon. A lifelong simulation using Monte Carlo methods is planned to explore long-term cost differences. Incremental cost-effectiveness ratios will be calculated, uncertainty will be assessed using probabilistic sensitivity analysis and non-parametric bootstrapping, and results will be presented using cost-effectiveness planes and acceptability curves. In addition, a budget impact analysis will assess the affordability of omitting routine seton placement from both societal and hospital perspectives over a 5-year time horizon under different implementation scenarios.

The trial is intended to determine whether direct sphincter-preserving surgery without prior loose seton is non-inferior to a staged strategy with preoperative loose seton in terms of fistula closure, while also evaluating differences in patient burden, quality of life, functional outcomes, and costs. If routine preoperative seton placement can be safely omitted, the results may support a shorter and less burdensome treatment pathway for patients and more efficient use of healthcare resources.