GM-CSF, Fosfomycin and Metronidazole for Pouchitis in Ulcerative Colitis Patients After Restorative IPAA Surgery

NCT ID: NCT04979832

Last Updated: 2023-01-26

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-09-06
• Study Completion Date: 2023-12-31

Brief Summary

This study will examine whether the application of GM-CSF, fosfomycin and metronidazole locally in the pouch is safe and effective in the treatment of pouchitis for patients with ulcerative colitis, and whether treatment changes the microbiome of the pouch.

Detailed Description

A definitive cure for patients with treatment-refractory ulcerative colitis is proctocolectomy with IPAA (restorative ileal pouch anal anastomosis). Up to 50% of all patients develop "pouchitis" within the first five years after surgery, an inflammatory condition that is as yet poorly understood and without official consensus on treatment. Treatment modalities include oral antibiotics as well as immunomodulators, steroids, probiotics and biological agents, but up to 20% of these patients develop chronic, treatment-resistant pouchitis, which can result in pouch failure and the need for reoperation with the possible creation of an ileostomy.

The etiology of pouchitis is thought to be similar to other inflammatory bowel diseases, in that genetic and bacterial factors, a compromised gastrointestinal barrier and immunological components seem to play a role. Its pathogenetic mechanisms seem to mimic Crohn's disease, in which smaller studies have shown some effect of systemically administered GM-CSF (granulocyte-macrophage colony stimulating factor) on the gut macrophage function in clearing microorganisms and maintaining the mucosal barrier.

The investigators hypothesize that GM-CSF will have an effect in the treatment of pouchitis because of its similarity to that of Crohn's disease. In order to maximize effect on the inflamed mucosa and minimize systemic side effects, the study drug will be administered locally in the pouch. In a safety and proof-of-concept intervention study, 50 µg GM-CSF will be combined with 400 mg Fosfomycin and 100 mg Metronidazole, to target both the suspected immunological as well as the bacterial role in the pathogenesis of pouchitis.

The effect on the pouch will be assessed endoscopically and histologically by taking biopsies that will also be examined for changes in the microbiome. Trial participants will be clinically examined and have blood samples taken to monitor for adverse reactions. The primary outcome measure will be an assessment of adverse reactions and tolerability of the drug. Secondary outcome measures will be a change in the pouchitis disease activity index (PDAI), a change in the microbial diversity, and a change in inflammatory markers.

This study is based on a non-randomized trial design with an open-label single group assignment.

Phase I The tolerability of treatment will be tested on 6 trial participants with pouchitis with a single dose of the combined medication applied endoscopically in the pouch. Endoscopy with the taking of biopsies will be performed before and one week after administration of the medication, as well as blood samples before and after the medication. After the follow-up endoscopy, the trial participant will receive standard oral metronidazole or ciprofloxacin treatment for 10 days.

Phase II Depending on effect of the first study, the second study plans for the treatment of 12 trial participants. Endoscopy with biopsies will be conducted with the first application of the study drug combination in the pouch, and afterward a daily dosage for another 6 days. Clinical and endoscopic control after 14 days with blood samples and biopsies will be done. After the follow-up endoscopy, the trial participant will receive standard oral metronidazole or ciprofloxacin treatment for 10 days.

Conditions

Pouchitis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Local administration of GM-CSF, fosfomycin and metronidazole in the pouch

Local administration of 50 micrograms GM-CSF, 400 milligrams fosfomycin and 100 milligrams metronidazole in the pouch.

In a Phase A of the trial, this will be applied as a single dose during endoscopy of the pouch. In Phase B of the trial, this will be applied as a first dose during endoscopy of the pouch, followed by 6 further daily doses for a total of 7 doses.

Group Type: EXPERIMENTAL

GM-CSF, fosfomycin and metronidazole

Intervention Type: DRUG

GM-CSF 50 micrograms Fosfomycin 400 milligrams Metronidazole 100 milligrams applied as a gel in the pouch

Interventions

GM-CSF, fosfomycin and metronidazole

GM-CSF 50 micrograms Fosfomycin 400 milligrams Metronidazole 100 milligrams applied as a gel in the pouch

Intervention Type: DRUG

Other Intervention Names

GM-CSF; Fosfomycin; Metronidazole

Eligibility Criteria

Inclusion Criteria

• Of any gender
• Over 18 years of age
• Have a previous diagnosis of ulcerative colitis
• Have had IPAA surgery, and
• Have been diagnosed with pouchitis
• Be able to understand and complete study procedures as determined by the investigator
• Be able to speak either Danish or English
• Be able to comply with study procedures for the length of the study
• Use a highly effective contraception method for the duration of the trial (until day 30 in Phase I and until day 37 in Phase II), such as implants, injectables, oral contraceptives, IUD (intrauterine device), sexual abstinence or vasectomized partner.

Exclusion Criteria

• Patients with a previous allergic reaction to GM-CSF, metronidazole or fosfomycin
• Patients who are currently under antibiotic treatment or have received antibiotic treatment within the past 30 days
• Patients currently pregnant or breastfeeding
• Patients with ASA IV classification (American Society of Anesthesiologists physical status classification)
• Patients with severe pulmonary disease
• Patients with autoimmune thrombocytopenia
• Patients with severe renal impairment (eGFR < 40 ml/min)
• Patients with alcohol use disorder or history of drug abuse
• Patients currently in treatment for any malignant or hematological disease
• Patients with a previous history of cancer will be excluded from the study (except for patients with well-treated and stabile cancer after a control period of more than two years).
• Patients with anticipated compliance problems as determined by the investigator

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Zealand University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ismail Gögenur, Professor

Role: PRINCIPAL_INVESTIGATOR

Zealand University Hospital

Locations

Zealand University Hospital

Køge, Region Sjælland, Denmark

Site Status: RECRUITING

Countries

Denmark

Central Contacts

Viviane Lin, MD

Role: CONTACT

vial@regionsjaelland.dk

60547025 ext. 0045

Ismail Gögenur, Professor

Role: CONTACT

igo@regionsjaelland.dk

26356426 ext. 0045

Facility Contacts

Viviane Lin, MD

Role: primary

vial@regionsjaelland.dk

60547025 ext. 0045

Ismail Gögenur, Professor

Role: backup

igo@regionsjaelland.dk

26356426 ext. 0045

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

2020-000609-10

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

REG-106-2020

Identifier Type: -

Identifier Source: org_study_id