Evaluation of Molgramostim, Fosfomycin, and Metronidazole for Pouchitis in Ulcerative Colitis Post-Restorative Ileal Pouch-Anal Anastomosis

The primary objective of this study is to evaluate the efficacy of a combined treatment regimen consisting of **GM-CSF** (molgramostim), **fosfomycin**, and **metronidazole** for the management of **pouchitis** in patients with ulcerative colitis who have undergone restorative ileal pouch-anal anastomosis surgery. This combination therapy is hypothesized to address the bacterial dysbiosis and inadequate immune response associated with pouchitis, conditions that mimic Crohn's disease and respond to similar therapeutic interventions. The clinical relevance of this study lies in its potential to offer a novel therapeutic approach for pouchitis, a condition that significantly impacts the quality of life in affected patients.

The clinical trial focuses on patients diagnosed with **pouchitis**, a condition that often mimics Crohn's disease. The study population includes individuals of any gender, aged 18 years and older, who have a previous diagnosis of ulcerative colitis and have undergone IPAA surgery. Participants must be able to understand and complete study procedures and communicate in either Danish or English. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are required to use a highly effective contraception method for the duration of the trial. The selection criteria ensure that participants can comply with study procedures for the entire study period.

The clinical trial is designed to evaluate the safety and efficacy of a combined treatment involving **molgramostim**, **fosfomycin**, and **metronidazole** for patients diagnosed with **pouchitis** following restorative ileal pouch anal anastomosis surgery for ulcerative colitis. This study is structured as a randomized, double-blind, controlled trial, ensuring that neither the participants nor the investigators are aware of the treatment allocations, thereby minimizing bias. The trial is expected to span from September 2021 to August 2027, with participant involvement lasting until day 30 in Phase I and until day 37 in Phase II.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, previous diagnosis of ulcerative colitis, and ability to comply with study procedures. Follow-up visits will be scheduled to monitor the primary endpoint, which is the change in the pouchitis disease activity index (PDAI), as well as secondary endpoints including changes in clinical, endoscopic, or histological PDAI, and various laboratory parameters. The end-of-study visit will assess the overall safety and efficacy of the treatment, including any serious adverse reactions.

Participants are expected to adhere to study procedures and use highly effective contraception methods throughout the trial. Conditions that may lead to early termination from the study include non-compliance with study procedures or the occurrence of serious adverse reactions. The trial aims to provide insights into the modulation of dendritic cells and inflammatory mechanisms, utilizing advanced techniques such as Nanostring nCounter analysis and flow cytometry. The study's findings will contribute to understanding the potential of this combination therapy in addressing bacterial dysbiosis and immune response inadequacies in pouchitis.

The clinical trial involves the administration of three experimental medications: **Metronidazole**, **Fosfomycin**, and **Molgramostim**. **Metronidazole** is provided in the form of an infusion, specifically designed for intra-abdominal use. The active substance, metronidazole, is of chemical origin. The dosage, frequency, and specific administration schedule are not detailed in the provided data. However, it is implied that the administration is topical within the pouch, as part of the combined treatment strategy for pouchitis in patients with ulcerative colitis following restorative ileal pouch anal anastomosis surgery.

**Fosfomycin** is administered as a solution for infusion, also intended for intra-abdominal use. The active substance, fosfomycin, is chemically derived. Similar to metronidazole, the specific dosage and administration frequency are not specified in the data. The use of fosfomycin in this trial is part of a combination therapy aimed at addressing bacterial dysbiosis and immune response inadequacies associated with pouchitis.

**Molgramostim** is provided as a lyophilisate and solvent for solution for injection, with intra-abdominal use as the designated route of administration. The active substance, molgramostim, does not have a specified origin in the data. The trial aims to explore the potential of molgramostim, in combination with metronidazole and fosfomycin, to modulate the immune response in pouchitis, drawing parallels to treatment strategies used in Crohn's disease. The specific dosing schedule and frequency for molgramostim are not detailed in the available information.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the provided data. Participant compliance monitoring and additional drug administration details are not specified. The trial's main objective is to evaluate the safety and proof-of-concept of this combined treatment approach in the specified patient population.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the change in the **Pouchitis Disease Activity Index (PDAI)**. Secondary endpoints include changes in clinical, endoscopic, or histological PDAI, as well as changes in median white blood cell count (WBC), C-reactive protein (CRP), creatinine, and liver enzymes from before the application of the study drug to seven days after application. Additionally, changes in microbial diversity in the pouch will be evaluated using 16S rRNA sequencing over the same timeframe. Safety assessments will focus on identifying serious adverse reactions or adverse reactions from the application of GM-CSF, metronidazole, and fosfomycin in the pouch. Furthermore, the modulation of dendritic cells and inflammatory mechanisms will be assessed using Nanostring nCounter analysis through mRNA expression and flow cytometry.