Surgical Closure vs Anti-TNF in the Treatment of Perianal Fistulas in Crohn's Disease (PISA-II): a Comprehensive Cohort Design (PISA-II)

Surgical Closure Versus Anti-TNF in the Treatment of Perianal Fistulas in Crohn's Disease (PISA-II): a Comprehensive Cohort Design

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 aim of this study is to compare radiological fistula healing at MRI after 18 months follow-up in Crohn's patients undergoing surgical closure to anti-TNF medication as treatment of perianal Crohn's fistulas.

Study design: In this multicenter comprehensive cohort design (CCD) Crohn's patients with a (re)active high perianal fistula will be allocated to anti-TNF for 1 year or surgical closure after 2 months under a short course of anti-TNF. Patients with a distinct preference will be treated accordingly, whereas only indifferent patients will be randomised in the usual way.

Main study parameters/endpoints: The primary outcome parameter is the number of patients with radiologically closed fistulas based on an evaluated MRI-score after 18 months. Secondary outcomes are clinical closure, number of patients undergoing surgical re-interventions and number of re-interventions, recurrences and quality of life based on the 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 6 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, power 80%). The maximal allowed skewed distribution is set at 1:4, which will result in a maximal sample size of 116 patients.

Study Overview

• Status: Completed
• Conditions: Crohn Disease; Perianal Fistula
• Intervention / Treatment: Drug: anti-tumour necrosis factor α antibodies; Procedure: Advancement plasty

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Noord Holland
    • Amsterdam-Zuidoost, Noord Holland, Netherlands, 1105AZ
      • Amsterdam UMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria

• ≥ 18 years
• (re-)active perianal fistula
• High perianal fistula tract (intersphincteric, transsphincteric, suprasphincteric) located in the upper two-thirds of the external sphincter or puborectal muscle
• Fistula with one internal opening (based on MRI imaging). The number of external fistulas does not have to be taken into account
• Written informed consent

4.3 Exclusion criteria

• Proctitis (defined as any active mucosal inflammation or ulcer > 5mm in the rectum)
• Anorectal stenosis (defined as the impossibility to introduce a proctoscope)
• Submucosal fistulas & low intersphincteric fistulas (lower one-third of external sphincter)
• Rectovaginal fistula
• Multiple internal openings
• Use of Anti-TNF medication for more than 3 months
• Previous failure of Anti-TNF treatment for perianal fistula
• Patients with a stoma
• Dementia or altered mental status that would prohibit the understanding and giving of informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Anti-TNF; Seton placement, followed by anti-TNF medication (infliximab or adalimumab) 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.	Drug: anti-tumour necrosis factor α antibodies; Biological drug
Active Comparator: Surgical closure; Seton placement, followed by anti-TNF medication in combination with a immunomodulator after ± 2 weeks. After 8-10 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.	Procedure: Advancement plasty; Surgical closure of the internal opening; Other Names: Ligation of the intersphincteric tract (LIFT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fistula closure	The number of patients with radiologically closed (completely fibrotic) fistula tract on MRI	at 1,5 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical closure	The number of patients with clinical closure, defined as closure of the external opening without discharge of pus or faeces on palpation	at 1,5 year
The number of patients undergoing surgical re-intervention	Amount of patients undergoing surgical re-intervention	at 1,5 year
The number of re-intervention	Amount of re-interventions	at 1,5 year
The quality of life of a patient	measured by the Perianal Disease Activity Index (PDAI score)	Every six months from baseline till 18 months
The number of recurrences	Amount of patients with a recurrence, defined as re-opening of the external opening after clinical closure	at 1,5 year

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: Willem Bemelman, MD PhD, Amsterdam UMC, location AMC

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2013
• Primary Completion (Actual): December 7, 2019
• Study Completion (Actual): June 7, 2021

Study Registration Dates

• First Submitted: April 10, 2019
• First Submitted That Met QC Criteria: June 1, 2024
• First Posted (Estimated): June 4, 2024

Study Record Updates

• Last Update Posted (Estimated): June 4, 2024
• Last Update Submitted That Met QC Criteria: June 1, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Anti-TNF; Crohn's disease; Perianal fistula; Advancement plasty; LIFT-procedure; Fistula closure; Comprehensive cohort design
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Pathological Conditions, Anatomical; Rectal Diseases; Inflammatory Bowel Diseases; Intestinal Fistula; Digestive System Fistula; Fistula; Crohn Disease; Rectal Fistula; Physiological Effects of Drugs; Immunologic Factors; Antibodies
• Other Study ID Numbers: NL66176.018.18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes