Preoperative Endoscopic Treatment With Fosfomycin and Metronidazole in Patients With Right-sided Colon Cancer and Colon Adenoma (MEFO-trial) · Trial · pharmadog
clinical trial · NCT04312360
Preoperative Endoscopic Treatment With Fosfomycin and Metronidazole in Patients With Right-sided Colon Cancer and Colon Adenoma (MEFO-trial)
Zealand University Hospital·phase2·completed·n = 28
Right-sided Colon CancerRight-sided Colon Adenomatherapeutic endoscopy with metronidazole and fosfomycin disodium
brief summary
Clinical studies have shown that patients with right-sided colon cancer have reduced progression-free and overall survival compared to patients with left-sided colon cancer. At the same time, patients with right-sided colon adenomas have a higher risk of developing interval cancers after endoscopic mucosal resection. Dysbiosis and known bacterial drivers play a significant role in the carcinogenesis of colorectal cancer, and may contribute to the growth of adenomas. Clinical studies have found biofilm formation and positive staining for Fusobacterium nucleatum (FN) in almost all right-sided colon cancers and adenomas. The composition of bacteria also in the normal mucosa in these two groups of patients has been found to be different from healthy controls.
Endoscopic preoperative antibiotic local treatment of the biofilm and tumors would theoretically result in decreased tumor mass, recovery of the mucosa, and a normalization of the immune response in the treated section of the colon. The oral administration of the antibiotic metronidazole in mice has shown to lower the tumor load (FN-positive xenograft tumors) and decrease in intratumoral abundance of the pro-carcinogenic bacteria, FN.
The aim of this study is to investigate the effect of local antibiotic treatment with fosfomycin and metronidazole on tumor characteristics and the colonic biofilm in patients with right-sided colon cancer or right-sided colon adenomas. This is a clinical proof-of-concept intervention study, and the investigators are to our knowledge the first group to look into local antibiotic treatment of biofilm in patients with colon cancer or colon adenoma. It is based on a non-randomized trial design with an open label single group assignment. There are two tracks depending on the pathology of the tumor: 1) patients with right-sided colon cancer; 2a) patients with right-sided colon adenoma. The intervention is a therapeutic endoscopy where the antibiotics fosfomycin and metronidazole are sprayed throughout the right colon section from caecum to the right colon flexure (100ml of gel contains 800mg of fosfomycin and 200mg of metronidazole). Patients will be included prospectively from the surgical department of Herlev University Hospital and Zealand University Hospital once having received oral and written information, followed by signing the consent. There will be a retrospective cohort of patients with colon adenoma from 2018 (track 2b). The investigators will retrieve the archived adenoma tissue as control tissue. In Clinical Trial, Track 1 and Track 2a will be registered as two different arms that use the same intervention, but the results from each arm later on is going to be reported in separate publications.
started
Jan 16, 2020
primary completion
Apr 13, 2022
completion
Jul 1, 2023
last updated
Sep 7, 2023
detailed description
Background Dysbiosis and known bacterial drivers play a significant role in the carcinogenesis of colorectal cancer. Among bacterial drivers, Fusobacterium nucleatum (FN) and the formation of biofilm on the surface of the colonic epithelium are considered pro-carcinogenic. The increased permeability of the mucosal layer and the invading bacteria in the colonic crypts and submucosal space result in genetic and epigenetic changes along with immune responses that are all important oncogenic factors. Clinical studies have found biofilm formation and positive staining for FN in almost all right-sided colon cancers and adenomas. Two studies compared the bacterial growth in normal mucosa from patients with and without adenoma. They found a different composition of bacteria in the normal mucosa from patients with adenomas in terms of richness, diversity and bacterial strains, thus indicating that the bacterial composition in the gut could contribute to the growth of adenomas and subsequently, adenocarcinomas.
Endoscopic preoperative local antibiotic treatment of the biofilm and tumors would theoretically result in decreased tumor mass, recovery of the mucosal layer, and a normalization of the immune response in the treated section of the colon. The oral administration of the antibiotic metronidazole in mice has already been shown to decrease tumor growth (FN-positive xenograft tumors) as well as a decrease in intratumoral FN abundance.
Investigational Medicinal Products In this study a gel containing the antibiotics fosfomycin and metronidazole will be sprayed endoscopically on the mucosa of the right hemicolon. The gel will be prepared on site by combining solutions of fosfomycin and metronidazole with a gel-forming gum.
Study objectives The aim of this study is to investigate the effect of local antibiotic treatment with fosfomycin and metronidazole on tumor characteristics and the colonic biofilm in patients with right-sided colon cancer or right-sided colon adenomas.
Study design This study is a clinical proof-of-concept intervention study. It is based on a non-randomized trial design with an open label single group assignment. There are two tracks depending on the pathology of the tumor: track 1, patients with right-sided colon cancer; track 2a, patients with right-sided colon adenoma. The intervention is a therapeutic endoscopy where the antibiotics fosfomycin and metronidazole are sprayed throughout the right colon section from caecum to the right colon flexure in a gel-forming mixture. Patients will be included from the surgical department of Herlev Hospital and Zealand University Hospital. There will be a retrospective cohort of patient with colon adenoma, track 2b.
official title
Preoperative Endoscopic Treatment With Fosfomycin and Metronidazole in Patients With Right-sided Colon Cancer and Colon Adenoma: a Clinical Proof-of-concept Intervention Study MEFO Trial
sourced from ClinicalTrials.gov · pharmadog mirrors structured fields, not the full protocol
Effect parameters For patients with right-sided colonic carcinomas and/or adenomas, the investigators hypothesize that endoscopic, preoperative antibiotic treatment in the right colon with a gel-forming spray containing fosfomycin and metronidazole will result in normalization of the colonic epithelium and immune response as well as a reduction in colonic biofilm formation often seen in these patients.
Trial structure and responsibilities The principal investigator (Astrid Bennedsen) is responsible for the preparation of the protocol, the Case Report Forms (CRFs), coordinating any meetings of the safety data monitoring committee as well as implementing decisions in the daily operations of the trial. Along with a team of co-investigators, the principal investigator will do the screening, recruitment, data collection and writing of the CRFs. The safety data monitoring committee consists of three members and will be impartial. They will overview the progress and the safety of the trial. The meetings of the safety data monitoring committee will take place every six months, but an extra meeting will be held in case of any severe adverse events or any other serious incidents during the trial. The trial will be monitored by a local GCP unit. The funding source had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results.
Stopping rules In case of serious side effects or adverse events, the data will be monitored and the trial stopped if there is any evidence of lack of safety regarding the intervention and the study drugs. Included are unexpected complications in relation to colon cancer surgery.
Study course This study has two tracks depending on the pathology of the colon tumor. When colon cancer is suspected, patients are referred to a colonoscopy during which biopsies are taken to confirm pathology indicating adenocarcinoma or benign pathology. There is a retrospective track 2b, where the investigators will retrieve FFPE adenoma tissue from up to 28 random patients operated with endoscopic mucosal resection in 2018. The trial drugs will be accounted for - both per site and per patient.
Selection and enrollment of participants Consecutive patients with endoscopically diagnosed right-sided colon adenomas or right-sided colon cancer tumors will be eligible for inclusion in the study. The investigators plan to include 14 patients with colon cancer (track 1) and 14 patients with colon adenoma (track 2a).
Also, 28 patients with colon adenoma will be included retrospectively (track 2b). The investigators will retrieve FFPE tissue from the resected mucosa bearing adenoma. They have had endoscopic mucosal resection performed in 2018 at Department of Surgery, Zealand University Hospital.
Recruitment of patients will be done consecutively according to the Research Ethics Committee's recommendations. Patients who are eligible for inclusion will receive both oral and written information about the study. At the end of the enrolment meeting the patient may sign the informed consent if they wish, and may also be given the time needed for consideration (at least 24 hours). The informed consent will be written in accordance with the Danish law. Patients will be informed if any changes in the study occur, as this might influence the patient's willingness to participate or the safety of the participating patients. The approved document will be updated accordingly.
A completed test person
A completed test person is defined as:
* Track 1: a patient who received the therapeutic endoscopy and had preoperative blood samples drawn on the operation day. Other than the interview on the day of the out-patient clinic visit (approximately postoperative day 14) there is no further study-related physical follow-up of the patient.
* Track 2a: a patient who received the therapeutic endoscopy and had preoperative blood samples drawn on the operation day. Other than the telephone interview on postoperative day 14 there is no further study-related physical follow-up on the patients.
Dropout procedure Dropout and withdrawals may happen at any point from the written consent till the preoperative blood sample on the operation day, and will not have any influence on the treatment of the patient.
Participating patients can withdraw from the study at any time for any reason. The patients will be informed of this right in accordance with the Helsinki Declaration.
The investigator can withdraw patients if the investigator feels the safety of the patient is compromised by the participation in the study. In that case, the investigator must inform the patient about the reason for withdrawal.
Patients who withdraw their consent will receive standard treatment. The reason, if stated, for the withdrawal will be noted in the CRFs. The number of dropouts and withdrawals will be reported. No further data will be collected from the patients withdrawing from the study; however, the previously collected data will be part of the final data analysis unless the patient specifically requests all data to be deleted.
Study interventions and procedures Intervention This is a non-randomized trial with an open label single group assignment. The intervention is a single therapeutic endoscopy during which patient´s right colon section will be sprayed with a predetermined volume of two component solutions, one containing fosfomycin and metronidazole, the other containing a gum that forms a gel on mixing with the former. During administration, the two components will be delivered through a dual channel colono-videoscope. The gel will form on the bowel wall and adhere to the mucosa.
