ASAPP Study - Topical 5-ASA as Prophylaxis for Pouchitis in Ulcerative Colitis Patients After Pelvic Pouch Surgery

Overview

Ulcerative colitis (UC) is a chronic intestinal disease, often debuting early in life, and affecting the colon and rectum. The therapy is mainly medical and based on 5-aminosalicylic acid (5-ASA) and steroids. The last 20 years numerous new advanced therapies have become available and introduced more and more early after diagnosis. Surgery is still needed in refractory disease and will cure most patients, while ending up with a stoma. There is conflicting data on whether advanced therapies are decreasing the need for surgery or not. Reconstruction of bowel continuity is usually possible but somehow performed in less than 50% of Swedish patients. Restorative proctectomy with ileal pouch (created of the last part of the small bowel) anal anastomosis (IPAA) is gold standard. As of this year it is centralized to 4 units in Sweden. One complication after IPAA is pouchitis, an inflammation in the pouch that behaves like UC. More than half of all patients will have at least one flare of pouchitis, and some will develop chronic or recurrent pouchitis. Recent publications have shown an increased risk of pouchitis after the introduction of advanced therapies, but the reasons for this are still unknown. Prophylactic therapy with 5-ASA after IPAA surgery have been suggested. All patients in Sweden going through IPAA surgery due to UC will be invited to be part of this randomized controlled study to evaluate if 5-ASA can diminish the risk of pouchitis in UC.

Purpose and aims There are four options (Fig 1) for patients after a colectomy in ulcerative colitis (UC)8. Ileal pouch anal anastomosis (IPAA) is gold standard for reconstruction of fecal continuity after colectomy for UC4. Pouchitis refers to a non-specific inflammation of the mucosa in the ileal pouch and resembles the previous UC5, despite the small bowel being affected rather than the colon and rectum. The cause of pouchitis is not fully understood and suggested causes include recurrence of UC due to colon metaplasia in the pouch, dysbiosis, short-chain fatty acid deprivation, genetic susceptibility, and immune dysregulation. The clinical features of pouchitis include increased stool frequency, rectal bleeding, abdominal cramping, urgency, tenesmus, night-time fecal seepage, and malaise and is associated with significant morbidity and low quality of life. It is the most common complication of IPAA surgery and is reported in 50 % of IPAA patients within the first two years of IPAA construction and up to 80% at some point5. About 20% will develop recurrent or even chronic pouchitis. Within 3 years 9% will be needing advanced therapy, increasing to 14% at 10 years, and some will need a diverting stoma or even a pouchectomy9. 5-aminosalicylic acid (5-ASA) is a well-established and safe treatment for UC and regarded as the basis therapy both as maintenance therapy and during a flare. There is limited knowledge on the effect of 5-ASA on pouchitis. A small study evaluated the effect of systemic sulfasalazine (5-ASA bound to sulfonamide) on acute pouchitis and found substantial reduction of symptoms18. In another study, systemic sulfazalasin was offered as primary pouchitis prophylaxis on a voluntary basis IPAA surgery7. Twenty patients (of 51) opted for prophylaxis and after a median follow-up of 68 months, 15% developed pouchitis compared to 68% in the group with no prophylaxis (p\<0.001). Based on this our hypothesis is that topical 5-ASA could reduce the risk for pouchitis in UC patients after IPAA surgery. Main research question: Does the risk of pouchitis decrease in patients with topical 5-ASA prophylaxis after IPAA surgery compared to topical placebo? Primary outcome: Any event of pouchitis at two years follow up defined as a Pouchitis Disease Activity Index (PDAI)19 of ≥7 in combination with pouchitis severity according to Endoscopic Pouch Score (EPS)20. The specific aims are to: 1. Compare time to first event of pouchitis between 5-ASA and placebo prophylaxis. 2. Number of patients having had pouchitis at 3 months, 6 months, 1 and 2 years from having a functioning pelvic pouch (closure of stoma if diverted at time of pouch creation). 3. Compare response rates of antibiotics and advanced therapy, respectively, in patients developing pouchitis after 5-ASA prophylaxis and placebo. 4. Assess patient satisfaction, health related quality of life (HRQoL), and bowel function and in relation to treatment strategy using questionnaires (Short Health Scale, SF36, Öresland score). 5. Assessment of mucosal permeability (by using an Ussing chamber) during follow-up and evaluate if this is affected by 5-ASA therapy and if impaired permeability is associated with subsequent development of pouchitis. Survey of the field The last 20 years numerous new advanced therapies have become available and introduced more and more early after UC diagnosis1. Surgery is still needed in refractory disease and will cure most patients. There is conflicting data on whether advanced therapies are decreasing the need for surgery or not1, 2. Restorative proctectomy with ileal pouch (created of the last part of the small bowel) anal anastomosis (IPAA) is gold standard4 and as of 1st of April this year (2026) it is centralized to four units in Sweden (by the National Board of Health and Welfare). A common complication after IPAA is pouchitis, an inflammation in the pouch that behaves like UC. More than half of all patients will have at least one flare of pouchitis, and some will develop chronic or recurrent pouchitis5. Recent publications have shown an increased risk of pouchitis after the introduction of advanced therapies, but the reasons for this are still unknown (6). Prophylactic therapy with 5-ASA after IPAA surgery have been suggested(7). Study design ASAPP is a prospective, national, multicenter, double-blind, randomized controlled trial. Adult patients with UC going through pouch surgery at any of the four Swedish national units will be asked to participate in the study. Most patients will have been treated with 5-ASA both systemically and topically before surgery and those previously intolerant to 5-ASA will be excluded from the study. Patients receive verbal and written information on pouchitis and the study protocol before asked for consent. Randomization will be performed at time of pouch surgery and patients will start either topical 5-ASA or placebo at time of discharge from hospital. Follow-up regarding symptoms, quality of life, and bowel function will be captured using REDCap. There are four time points of follow-up: 3 and 6 months, 1 and 2 years from having the pouch functioning without any diverting stoma. If patients develop symptoms of pouchitis in between these time points an extra outpatient evaluation will be initiated. Endoscopy of the pouch (EPS score)(20) is performed and PDAI are determined at every timepoint(19). The patient is invited through REDCap to complete questionnaires on symptoms, quality of life, and bowel function. If a patient presents with symptoms of pouchitis between scheduled follow-up visits, a PDAI and endoscopy assessment will be assessed. For patients with three or more previously endoscopy-confirmed episodes of pouchitis, the presence of typical pouchitis symptoms alone may be considered sufficient to define an episode of pouchitis. Patients developing pouchitis will receive treatment according to standard clinical practice, i.e. course of antibiotics and in case of non-response, recurrent episodes or development of chronic pouchitis patients will be assessed for advanced therapy. Research questions Primary research question: Does the risk of pouchitis decrease in patients with topical 5-ASA prophylaxis after IPAA surgery compared to topical placebo? Population: Adult patients with UC who have previously been going through or planned to go through a colectomy and who have opted for restorative surgery with an IPAA. Intervention: Topical 5-ASA after IPAA reconstruction. Control: Topical placebo. Outcome: Time to first event of pouchitis during the first two years of follow-up. Secondary research questions address number and severity of pouchitis flares, response to pouchitis treatment, need for diverting stoma or pouch excision, longitudinal HRQoL, and bowel function. In a subset of patients mucosal permeability(21) will be evaluated over time and assessed in relation to treatment arm (5-ASA vs placebo) and subsequent risk of pouchitis. Material: Patient selection - population, sample The target population consists of adult patients with UC who are planned for reconstruction with IPAA. All four units with a national license to perform restorative surgery in IBD will be recruiting patients. Patients with concomitant primary sclerosing cholangitis (PSC) or previous intolerance to 5-ASA will be excluded. Variables and measures The primary outcome is time to first event of pouchitis within two years follow up defined as a PDAI of ≥7 in combination with pouchitis according to EPS(19, 20). Secondary outcomes include number of episodes with pouchitis during follow-up, response to potential pouchitis treatment, bowel function (Öresland score), and HRQoL (SF36, SHS). Patients included in Linköping will also have the mucosal permeability investigated (Ussing chamber)(21). Estimated sample size and power The planned sample size is approximately 110 patients. Based on the previous publication the study is powered to detect a clinically relevant decrease in pouchitis from 50% in the placebo group to 15% in the 5-ASA group(7). To detect such difference at an accepted alfa level of 0.05 and 90% power would require a total of 84 evaluable patients (42 i each group). Given that all patients may not be eligible for the study due to postoperative complications (10%), PSC (5%) or intolerance to 5-ASA (\<10%) and loss to follow-up (\<10%) we would need to approach approximately 110 patients scheduled for IPAA surgery. Statistical methods The primary endpoint, any event of pouchitis during the study period will be evaluated using Logistic regression. The exposure will be defined at randomization, and an intention to treat analysis will be applied. Time to first pouchitis episode will be compared using Cox regression analysis and Kaplan-Meier graphs. Severity of pouchitis will be compared using Mann-Whitney U-test. Frequency of pouchitis will be compared using Poission regression. Statistical analysis will be conducted in R. Permeability sub-study In a sub-study at the Linköping University Hospital patients will be asked to have biopsies taken from the pouch at time of every endoscopy. Biopsies will be taken fresh to the lab for investigation of mucosal permeability using the Ussing chamber(21). Feasibility Ethical approval and approval from the Medical Products Agency are in progress and preparation of placebo suppositories is initiated. In regards of the number of IPAA operations performed annually in Sweden we should be able to complete the inclusion within three years. Time plan and milestones * Year 1: Regulatory approvals study initiation. * Years 1-3: Recruitment from the four units (approx. 110 patients), completion of 6-month follow-ups. Interim analysis after approximately 40 patients completed the 6-month assessment. * Year 4: Long-term follow-up. * Year 5: Analyses, reporting and dissemination of results. Long-term follow-up continued (up to two years). Risk mitigation Potential risks include slower-than-expected recruitment and loss to follow-up. These risks are mitigated through a multicenter design with all Swedish centers participating, integration of recruitment into routine care, and continuous monitoring of study progress. Regulatory and logistical risks are managed through established clinical research support structures at participating hospitals. We will hold regular discussions with all sites at time of our scheduled monthly multidisciplinary team meetings. Equipment The equipment needed is part of the standard care at all participating hospitals (endoscopy). Regarding the translational part performed in Linköping all equipment is already available. Need for research infrastructure No further needed than previously described. References (numbered according to main application) 1. Young, J.C., et al., Temporal trends in characteristics and management of inflammatory bowel disease. Scandinavian Journal of Gastroenterology, 2025. 60(5): p. 421-429. 2. Lundberg Båve, A., et al., Colectomy in patients with ulcerative colitis is not associated to future diagnosis of primary sclerosing cholangitis. United European Gastroenterol J, 2023. 3. Worley, G., et al., Restorative surgery after colectomy for ulcerative colitis in England and Sweden: observations from a comparison of nationwide cohorts. Colorectal Dis, 2018. 20(9): p. 804-812. 4. Adamina, M., et al., ECCO Guidelines on Therapeutics in Ulcerative Colitis: Surgical Treatment. J Crohns Colitis, 2026. In press. 5. Kayal, M., et al., ECCO Topical Review on Pouch Disorders. J Crohns Colitis, 2025. 19(7). 6. Barnes, E.L., et al., Increasing Incidence of Pouchitis Between 1996 and 2018: A Population-Based Danish Cohort Study. Clin Gastroenterol Hepatol, 2023. 21(1): p. 192-199 e7. 7. Scaioli, E., et al., Sulfasalazine in Prevention of Pouchitis After roctocolectomy with Ileal Pouch-Anal Anastomosis for Ulcerative Colitis. Dig Dis Sci, 2017. 62(4): p. 1016-1024. 8. Myrelid, P. and T. Øresland, A reappraisal of the ileo-rectal anastomosis in ulcerative colitis. J Crohns Colitis, 2015. 9(6): p 433-8 9. Barnes, E.L., et al., The Natural History After Ileal Pouch-Anal Anastomosis for Ulcerative Colitis: A Population-Based Cohort Study From the United States. Official journal of the American College of Gastroenterology \| ACG, 2024\. 119(11): p. 2267-2274. 10. Dixon, S.W., et al., 5-Aminosalicylic acid inhibits stem cell function in human adenoma-derived cells: implications for chemoprophylaxis in colorectal tumorigenesis. British Journal of Cancer, 2021. 124(12): p. 1959-1969. 11\. Rubin, D.T., et al., Aminosalicylate Therapy in the Prevention of Dysplasia and Colorectal Cancer in Ulcerative Colitis. Clinical Gastroenterology and Hepatology, 2006. 4(11): p. 1346-1350. 12. Makkar, R. and S. Bo, Colonoscopic perforation in inflammatory bowel disease. Gastroenterol Hepatol (N Y), 2013. 9(9): p. 573-83. 13\. Druvefors, E., et al., Impaired Fertility in Women With Inflammatory Bowel Disease: A National Cohort Study From Sweden. J Crohns Colitis, 2021. 15(3): p. 383-390. 14\. Torres, J., et al., European Crohn's and Colitis Guidelines on Sexuality, Fertility, Pregnancy, and Lactation. J Crohns Colitis, 2023. 17(1): p. 1-27. 15\. MacDonald, S., et al., Complications and functional outcomes after ileo-anal pouch excision-a systematic review of 14 retrospective observational studies. International Journal of Colorectal Disease, 2021. 36(4): p. 677-687. 16\. Cavallaro, P., et al., Patients Undergoing Ileoanal Pouch Surgery Experience a Constellation of Symptoms and Consequences Representing a Unique Syndrome: A Report From the Patient-Reported Outcomes After Pouch Surgery (PROPS) Delphi Consensus Study. Ann Surg, 2021. 274(1): p. 138-145. 17. Gerdin, L., et al., The Swedish Crohn Trial: A Prematurely Terminated Randomized Controlled Trial of Thiopurines or Open Surgery for Primary Treatment of Ileocaecal Crohn's Disease. J Crohns Colitis, 2016. 10(1): p. 50-4. 18 Belluzzi A., et al. Pilot study: the use of sulfasalazine for the treatment of acute pouchitis. Aliment Pharmacol Ther. 2010;31(2):228-32. 19\. Sandborn WJ., et al., Pouchitis after ileal pouch-anal anastomosis: a Pouchitis Disease Activity Index. Mayo Clin Proc. 1994;69(5):409-15. 20\. Barnes EL, et al. Development of the Endoscopic Pouch Score for Assessment of Inflammatory Conditions of the Pouch. Clinical Gastroenterology and Hepatology. 2023;21(6):1663-6.e3. 21 Persborn, M., et al., The effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis. Aliment Pharmacol Ther, 2013. 38(7): p. 772-83.