Clinical trial NCT04979832: GM-CSF, Fosfomycin and Metronidazole for Pouchitis in Ulcerative Colitis Patients After Restorative IPAA Surgery
Official title: A Combined Treatment With GM-CSF, Fosfomycin and Metronidazole for Pouchitis in Ulcerative Colitis Patients After Restorative Ileal Pouch Anal Anastomosis Surgery
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Pouchitis
Lead sponsor: Zealand University Hospital
Sponsor class: OTHER
First posted: 2021-07-28
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Phase 1: safety study, Determine serious adverse reactions or adverse reactions from the application of GM-CSF, metronidazole and fosfomycin in the pouch
timeFrame: 30 days after first application of study drug
measure: Phase 2: Proof of concept study, Change in the pouchitis disease activity index (PDAI)
timeFrame: 14 days after first application of the study drug
Secondary outcomes:
measure: Phase 1: Change in the pouchitis disease activity index (PDAI)
timeFrame: Within 7 days after application of the study drug
measure: Phase 1: Number of trial participants with a change in median white blood cells after treatment
timeFrame: Within 7 days after application of the study drug
measure: Phase 1: Number of trial participants with a change in median CRP after treatment
timeFrame: Within 7 days after application of the study drug
measure: Phase 1: Number of trial participants with a change in median creatinine after treatment
timeFrame: Within 7 days after application of the study drug
measure: Phase 1: Number of trial participants with a change in median liver enzymes after treatment
timeFrame: Within 7 days after application of the study drug
measure: Phase 1: Change in microbial diversity in the pouch using 16S rRNA sequencing
timeFrame: Within 7 days after application of the study drug
measure: Phase 2: Change in the clinical, endoscopic or histological PDAI
timeFrame: 14 days after first application of the study drug
measure: Phase 2: Number of trial participants with a change in median white blood cells after treatment
timeFrame: 14 days after first application of the study drug
measure: Phase 2: Number of trial participants with a change in median CRP after treatment
timeFrame: 14 days after first application of the study drug
measure: Phase 2: Number of trial participants with a change in median creatinine after treatment
timeFrame: 14 days after first application of the study drug
measure: Phase 2: Number of trial participants with a change in median liver enzymes after treatment
timeFrame: 14 days after first application of the study drug
measure: Phase 2: Change in microbial diversity in the pouch using 16S rRNA sequencing
timeFrame: 14 days after first application of the study drug
measure: Phase 2: Determine serious adverse reactions or adverse reactions from the application of GM-CSF, metronidazole and fosfomycin in the pouch
timeFrame: 37 days after first application of the study drug
Other outcomes:
Locations:
city: Køge
country: Denmark
facility: Zealand University Hospital
state: Region Zealand
Study officials:
affiliation: Zealand University Hospital
name: Ismail Gögenur, Professor
role: PRINCIPAL_INVESTIGATOR
References: