GUselkumAb inteRvention and DIet evaluAtioN for Pouchitis

Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) is considered the procedure of choice in patients with ulcerative colitis (UC) refractory to medical therapy or with neoplasia. The most common complication after IPAA is the development of pouchitis. Pouchitis is clinically characterized by variable symptoms including increased stool frequency, altered consistency, bloody stools, abdominal cramping, urgency, and incontinence. Symptomatic pouchitis longer than four weeks is considered chronic pouchitis.

The conventional treatment for acute and chronic pouchitis is antibiotics, such as metronidazole and ciprofloxacin. The disease course of antibiotic responsive pouchitis may evolve into antibiotic dependent (requiring antibiotic maintenance therapy) pouchitis and then antibiotic refractory (no response to antibiotic treatment) pouchitis. Although many patients respond to antibiotic therapy, there is also evidence that suggest that aberrant regulation of the mucosal immune system might play a part in the pathogenesis of pouchitis arising from an abnormal mucosal immune response to a dysbiosis of the pouch microbiota. If individuals fail to respond to antibiotics, anti-tumor necrosis factor (anti-TNF) agents and vedolizumab have been proposed for the treatment of chronic pouchitis.

Guselkumab, an interleukin-23 (IL-23) p19 subunit antagonist monoclonal antibody, is proven to be efficacious in patients with moderately-to-severely active UC. Efficacy of guselkumab in treating UC has been shown in multiple large clinical trials. However, patients with pouchitis were never the targeted population and were even often excluded from the trials.

Pouchitis becomes a chronic problem with a huge impact in the quality of life of these patients. The incidence of pouchitis has been rising in the last decades. This increase might be explained by a change in dietary habits of this population.

This open label single center trial at UZ Leuven aims to evaluate the efficacy and safety of guselkumab in the treatment of chronic antibiotic refractory pouchitis during a 48-week treatment period, with or without a dietary intervention. Twenty subjects with a proctocolectomy and IPAA for UC who have developed chronic or relapsing pouchitis will be enrolled.

Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) is considered the procedure of choice in patients with ulcerative colitis (UC) refractory to medical therapy or with neoplasia. The most common complication after IPAA is the development of pouchitis. Pouchitis is clinically characterized by variable symptoms including increased stool frequency, altered consistency, bloody stools, abdominal cramping, urgency, and incontinence. Between 50% and 80% of those with an IPAA will experience pouchitis symptoms at any given moment with 10% of patients developing a chronic antibiotic refractory pouchitis. Symptomatic pouchitis for less than four weeks is considered acute pouchitis, while symptomatic pouchitis longer than four weeks is considered chronic pouchitis. Additionally, relapsing pouchitis can also occur when there are three or more episodes per year.

The conventional treatment for acute and chronic pouchitis is antibiotics, such as metronidazole and ciprofloxacin. The clinical response of pouchitis to treatment with antibiotics such as metronidazole or ciprofloxacin, suggests that fecal stasis, Clostridium difficile infection, bacterial overgrowth or dysbiosis (qualitative or quantitative alterations in the bacterial communitiy) may be triggers. The disease course of antibiotic responsive pouchitis may evolve into antibiotic dependent (requiring antibiotic maintenance therapy) pouchitis and then antibiotic refractory (no response to antibiotic treatment) pouchitis. Although many patients respond to antibiotic therapy, there is also evidence that suggest that aberrant regulation of the mucosal immune system might play a part in the pathogenesis of pouchitis arising from an abnormal mucosal immune response to a dysbiosis of the pouch microbiota. If individuals fail to respond to antibiotics, anti-tumor necrosis factor (anti-TNF) agents and vedolizumab have been proposed for the treatment of chronic pouchitis. Recently, vedolizumab has been shown to be efficacious in treating chronic pouchitis with remission rates of 31% at week 14. Nevertheless, the treatment of chronic pouchitis remains an unmet need for patients with inflammatory bowel diseases (IBD).

Guselkumab, an interleukin-23 (IL-23) p19 subunit antagonist monoclonal antibody, is proven to be efficacious in patients with moderately-to-severely active UC. In the phase II GALAXI 1 trial (309 patients with UC, 2020), intravenous treatment with 200 mg, 600 mg or 1,200 mg guselkumab at weeks 0, 4 and 8 showed significantly greater reductions from baseline CDAI, outcomes of clinical response, clinical remission, Patient-Reported Outcome-2 (PRO-2) remission, clinical biomarker response and endoscopic response at week 12 compared with intravenous placebo. The QUASAR study (313 patients with UC, 2022), a Phase 2b/3 randomized, double-blind, placebo-controlled trial, demonstrated superiority of guselkumab to placebo for clinical response during induction at week 12 in patients with UC. Guselkumab also met key secondary endpoints of clinical remission, symptomatic remission, endoscopic improvement, and histo-endoscopic mucosal improvement. The efficacy and safety of guselkumab in patients with UC were further studied in the exploratory Phase 2a VEGA trial (214 patients with UC, 2023) evaluating combination treatment of guselkumab and golimumab during induction. Combination therapy was significantly more effective than either drug alone for clinical remission and endoscopic improvement. A meta-analysis (36 studies with 14270 patients with UC, 2024) comparing the relative efficacy of biologics and small molecules, proved Guselkumab to rank high in achieving clinical remission, endoscopic improvement and remission, and histological remission in patients with moderate to severe UC. Efficacy of guselkumab in treating UC has been shown in multiple large clinical trials. However, patients with pouchitis were never the targeted population and were even often excluded from the trials.

Pouchitis becomes a chronic problem with a huge impact in the quality of life of these patients. The incidence of pouchitis has been rising in the last decades. This increase might be explained by a change in dietary habits of this population. Interestingly, lower fruit consumption has been associated with higher risk of pouchitis. Moreover, food colorants have been associated with colitis in mice with higher IL-23 expression.

This open label single center trial at UZ Leuven aims to evaluate the efficacy and safety of guselkumab in the treatment of chronic antibiotic refractory pouchitis during a 48-week treatment period, with or without a dietary intervention. Twenty subjects with a proctocolectomy and IPAA for UC who have developed chronic or relapsing pouchitis will be enrolled.

Eligibility Criteria:
Inclusion Criteria:

1. Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures
2. At least 18 years of age at the time of signing the Informed Consent Form (ICF)
3. Use of highly effective methods of birth control; defined as those that, alone or in combination, result in low failure rate (i.e., less than 1% per year) when used consistently and correctly; such as implants, injectables, combined oral contraceptives, some IUDs, true sexual abstinence (i.e. refraining from heterosexual intercourse during the entire period of risk associated with the Trial treatment(s)) or commitment to a vasectomised partner.
4. Participant with a proctocolectomy and IPAA for UC who heveloped chronic or relapsing pouchitis, defined as mPDAI score ≥5 and a minimum endoscopic subscore of 2 (outside the staple or suture line) with either:

   1. ≥2 recurrent episodes within 1 year prior to the screening visit, each treated with ≥2 weeks of antibiotic or other prescription therapy, or
   2. patients treated with maintenance antibiotic therapy taken continuously for four consecutive weeks before the screening visit and who are refractory to this antibiotic therapy, or
   3. previously failure of another biologic therapy to treat chronic pouchitis.
5. The subject agrees to take ciprofloxacin (500 mg twice daily) on Day 1 and through Week 4, regardless of the previous treatment and to stop any previous antibiotic therapy on Day 1 of the study. For patients who did previously not tolerate quinolone therapy, an alternative antibiotic therapy between Day 1 and Week 4 with metronidazole (500 mg three times a day) will be allowed. (Additional courses of antibiotics will be allowed, as needed, for flares after Week 16.)

All participants that are considered for Trial participation, per the above criteria will be documented via applicable log forms in Investigator Site File (including Screen Failures).

Exclusion Criteria:

1. Crohn's disease (CD), CD-related complications of the pouch (pouch fistula, pouch strictures, ulcerations in the pre-pouch ileum without pouchitis), irritable pouch syndrome (IPS), isolated or predominant cuffitis, infectious pouchitis, diverting ostomy or mechanical complications of the pouch
2. Previous treatment with an anti-IL12/23 or an anti-IL23 antibody
3. Any investigational or approved biologic agent within 30 days of screening
4. Nonbiologic investigational therapy or JAK inhibitors within 30 days prior to screening
5. Active or untreated latent tuberculosis (TB). In case of a newly identified positive diagnostic TB test result (defined as a positive tuberculin skin test) , active TB has to be ruled out and appropriate treatment for latent TB has to be initiated for a minimum of 4 weeks prior to the first administration of study medication.
6. Chronic hepatitis B virus (HBV)\* infection, chronic hepatitis C virus (HCV)\*\* infection, a known history of human immunodeficiency virus (HIV) infection (or is found to be seropositive at screening) or subject is immunodeficient (e.g., due to organtransplantation, history of common variable immunodeficiency, etc). \* Subjects who are positive for hepatitis B virus surface antigen (HBsAg) will be excluded. For subjects who are negative for HBsAg but are positive for either surface antibodiesand/or core antibodies, HBV DNA polymerase chain reaction will be performed and if anytest result meets or exceeds detection sensitivity, the subject will be excluded.\*\* If subject is HCV antibody positive, then a viral load test will be performed. If the viralload test is positive then the subject will be excluded.
7. Active severe infection (eg sepsis, cytomegalovirus, listeriosis or C. difficile)
8. The subject has allergies to and/or contraindications for ciprofloxacin and metronidazole
9. Participant has a history of malignancy or current malignancy, except for the following: adequately treated non-metastatic basal cell skin cancer, squamous cell skin cancer and cervical carcinoma in situ. Subjects with a remote history of malignancy (e.g., \>10 years since completion of curative therapy without recurrence) will be considered based on the nature of the malignancy and the therapy.
10. Any disorder or laboratory abnormalities which in the Investigator's opinion might jeopardise the participant's safety or compliance with the protocol.
11. Any prior or concomitant treatment(s) that might jeopardise the participant's safety or that would compromise the integrity of the Trial (see list in 5.3).
12. Female who is pregnant, breast-feeding or intends to become pregnant before, during, or within 15 weeks after the last dose of study drug; or intending to donate ova during such time period or is of child-bearing potential and not using an adequate, highly effective contraceptive or males who want to make their partner pregnant or intends to donate sperm during the course of this study or for 18 weeks after the last dose of study drug
13. Participation in another interventional Trial with an investigational medicinal product (IMP) or device.

Participants who meet one or more of the above exclusion criteria must not proceed to be enrolled/randomized in the Trial and will be identified via applicable log forms in Investigator Site File.