Endoscopic Application of GM-CSF, Fosfomycin, and Metronidazole in Pouchitis, a Phase I Safety and Pilot Study.

BACKGROUND: Inflammation of the pouch is common in patients with ulcerative colitis after ileal pouch anal anastomosis surgery. Up to 20% of patients develop chronic or treatment refractory pouchitis. AIMS: We aimed to test the safety and efficacy of applying a combination drug in the pouch. METHODS: We conducted a single-arm, open-label phase I study. Patients with pouchitis received a single dose of 50 µg granulocyte-macrophage colony-stimulating factor (GM-CSF), 400 mg of fosfomycin, and 100 mg of metronidazole endoscopically in the pouch. The primary outcome was the occurrence of adverse events, while secondary outcomes were changes in the Pouchitis Disease Activity Index (PDAI), laboratory parameters, bacterial composition, and mucosal gene expression patterns. RESULTS: Six patients were included from August 2021 to December 2022 at Zealand University Hospital. One serious adverse event occurred in the form of a hospitalization for dehydration, deemed unrelated to the study drug. PDAI decreased on average 2 points, with 2 (33.3%) patients achieving clinical remission (PDAI < 7), while laboratory parameters remained similar. Bacterial composition of the pouch mucosa did not change significantly. Gene expression analysis indicated enhanced immune cell communication, reduced proteasome activity, and a shift from innate to adaptive immunity, with fewer dendritic cells and more B cells in the pouch mucosa after treatment. CONCLUSIONS: The administration of GM-CSF, fosfomycin, and metronidazole in the pouch appears to be safe in patients with pouchitis and results in immunological changes suggesting a reduction in inflammation, ClincialTrials.gov number, NCT04979832.