Surgical closure versus anti-TNF in the treatment of perianal fistulas in Crohn’s Disease (PISA-II): a comprehensive cohort design

SUMMARY

Rationale: Currently, the treatment of Crohn's patients with perianal fistulas predominantly exists of anti-TNF medication. However, its efficiency has never been directly compared to surgical closure of the perianal fistula. The primary objective of this study is to determine the optimal treatment for perianal Crohn’s fistulas by comparing two standard treatment strategies.

Methods: In this multicenter comprehensive cohort design Crohn’s patients with a (re)active high perianal fistula will be allocated to anti-TNF for 1 year or surgical closure under a short course of anti-TNF (4 months). Patients with a distinct treatment preference will be treated accordingly, whereas only indifferent patients will be randomized in the usual way. The primary outcome parameter is the number of patients with a radiologically closed fistulas on MRI after 18 months. Secondary outcomes are clinical closure, re-interventions, recurrences and quality of life (QoL) based on Perianal Disease Activity Index (PDAI).

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: All patients will receive one of the two standard treatment approaches that are currently used for Crohn's fistulas. All effort has been performed to ensure most optimal treatment, according to best available evidence and current guidelines. Since there is no experimental study-arm, there are no additional risks associated with participation. During the study, the medical staff and trial nurses will monitor the necessity of surgical interventions and hospitalizations. At baseline and after 18 months all patients will undergo a MRI to score the fistula. Secondary outcome parameters will be assessed during visits to the outpatient clinic or telephone consultations at baseline and at intervals of 3 months for the duration of the study period. Every six months patients were asked to fill out the PDAI questionnaire with their physician. Based on the available literature, radiological closure of fistulas is expected in 40% of patients in the surgical closure group compared to 15% in the anti-TNF group. The increase in closure rate from 15% to 40% is considered clinically relevant. Due to the combination of a preference and randomized cohort, the appropriate sample size to detect this 25% difference is flexible and is adjusted for a skewed distribution. The minimal sample size, in case of a 1:1 treatment allocation, needed to detect this difference with a Chi-square test equals 86 patients (alpha 0.05, and power 80%). The maximal allowed skewed distribution is set at 1:4, which will result in a maximal sample size of 116 patients.

It is hypothesized that the surgical closure arm will result in an increased radiological fistula closure rate on MRI compared to the anti-TNF treatment arm (40 versus 15% respectively).

Patients visit the outpatient clinic regularly, as part of standard treatment. Additionally, patients will be contacted by telephone (CRF) every ± 3 months by a local investigator, trial nurse, or the Amsterdam UMC study coordinator to assess medication usage, complications, additional interventions, re-admissions, duration of hospital stay and visits to the outpatient clinic.

Every 6 months, the patient will fill out the PDAI together with the gastroenterologist or surgeon at that time point. The PDAI is the gold standard for evaluating the severity of perianal disease. It includes five items: discharge, pain, restriction of sexual activity, type of perianal disease, and degree of induration.

The following groups will be compared:
Group I: Seton placement, followed by anti-TNF medication in combination with a immunomodulator after ± 2 weeks. The seton will be removed after ± 6 weeks. Continuation of anti-TNF medication for at least 1 year, after one year continuation is at the discretion of treating physician.
Group II: Seton placement, followed by anti-TNF medication in combination with a immunomodulator after ± 2 weeks. After 8-12 weeks removal of seton and surgical closure (advancement plasty or ligation of the intersphincteric tract (LIFT) procedure). Anti-TNF in combination with a immunomodulator will be stopped after ± 4 months.