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Preoperative Endoscopic Treatment With Fosfomycin and Metronidazole in Patients With Right-sided Colon Cancer and Colon Adenoma (MEFO-trial) (MEFO)

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ClinicalTrials.gov Identifier: NCT04312360
Recruitment Status : Recruiting
First Posted : March 18, 2020
Last Update Posted : March 26, 2020
Sponsor:
Collaborators:
Costerton Biofilm Center
Reponex Pharmaceuticals A/S
Region Zealand
Information provided by (Responsible Party):
Zealand University Hospital

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.


Condition or disease Intervention/treatment Phase
Right-sided Colon Cancer Right-sided Colon Adenoma Drug: therapeutic endoscopy with metronidazole and fosfomycin disodium Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:

The same intervention will apply to both arms of this study, the only difference is the patient group which receives the treatment.

In Clinical Trial, Track 1 and Track 2a will be registered as two different arms, but the results from each arm later on is going to be reported in separate publications.

Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 16, 2020
Estimated Primary Completion Date : October 22, 2021
Estimated Study Completion Date : November 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Endoscopy

Arm Intervention/treatment
Experimental: intervention track 1

14 patient with right-sided colon cancer receive intervention before the hemicolectomi.

both arms of this study use the same intervention.

Drug: therapeutic endoscopy with metronidazole and fosfomycin disodium
therapeutic endoscopy where the two drugs: metronidazole and fosfomycin disodium are sprayed through out the right colon section (from caecum to right colon flexure). This intervention is going to be performed on patients in both track 1 and track 2a.

Experimental: intervention track 2a

14 patient with right-sided colon adenoma receive intervention before the endoscopic mucosa resection.

both arms of this study use the same intervention.

Drug: therapeutic endoscopy with metronidazole and fosfomycin disodium
therapeutic endoscopy where the two drugs: metronidazole and fosfomycin disodium are sprayed through out the right colon section (from caecum to right colon flexure). This intervention is going to be performed on patients in both track 1 and track 2a.




Primary Outcome Measures :
  1. Change in the bacterial biofilm depth adherent to the colonic epithelium [ Time Frame: 10 - 30 months ]
    A quantitative change in the bacterial biofilm adherent to the colonic epithelium of the resected colon adjusted for baseline level found before the intervention through fluorescence in situ (FISH) technique. The specific measurement variable is biofilm depth in μm. The method of aggregation will be means.

  2. quantitative change in bacterial biomass adherent to the colonic epithelium [ Time Frame: 10 - 30 months ]
    A quantitative change in the bacterial biomass adherent to the colonic epithelium of the resected colon adjusted for baseline level found before the intervention through fluorescence in situ (FISH) technique. The specific measurement variable is biofilm mass in ng/cm^2. The method of aggregation will be means.

  3. Change in gene expression (Exploratory primary outcome 1) [ Time Frame: 10 - 30 months ]
    - The determination of differences in translational markers present in the resected tumor tissue adjusted for the level seen at the baseline (the therapeutic colonoscopy) through a principal component analysis (PCA). The translational markers of interest are tumor markers, markers of the microenvironment and the immune response. The analyses will be performed using the PanCancer IO 360TM Gene Expression Panel (nanoString).

  4. Change in bacterial composition (Exploratory primary outcome 2) [ Time Frame: 10 - 30 months ]
    - The determination of a change in the bacterial composition adjusted for the bacteria found at baseline before the intervention through fluorescence in situ (FISH) technique and sequencing with Metagenome.


Secondary Outcome Measures :
  1. Differences in the presence of known bacterial drivers for right-sided colon og adenoma cancer in track1 [ Time Frame: 10 - 30 months ]
    Differences in the presence of known bacterial drivers such as Fusobacterium nucleatum, Enterococcus faecalis, Bacteroides Fragilis, Escherischia coli, and Porphyromonas in the tumor samples from preoperative biopsies and the resected colon.

  2. Differences in gene expression in the normal mucosa from preoperative in biopsies and the resected colon in track1 [ Time Frame: 10 - 30 months ]
    Differences in gene expression in the normal mucosa from preoperative biopsies and the resected colon using the PanCancer IO 360TM Gene Expression Panel (nanoString).

  3. Differences in gene expression in the preoperative and operative blood samples in track1 [ Time Frame: 10 - 30 months ]
    Differences in gene expression in the preoperative and operative blood samples determined by the nCounter® PanCancer Immune Profiling Panel (nanoString).

  4. The immunological assessment of tumor in track1 [ Time Frame: 10 - 30 months ]
    Assessment of the immunological response using immunoscore. A binary outcome of either high or low immunoscore

  5. The pathological assessment of tumor in track1 [ Time Frame: 10 - 30 months ]
    The pathological assessment of tumor: tumor type, grade of dysplasia, TNVM-stage, MSI- status.

  6. Occurence of biofilm present on the colon cancer tumor [ Time Frame: 10 - 30 months ]
    A microbiological assessment of the biofilm present on the tumor in track 1. This will be reported as a binary outcome.

  7. The pathological assessment of the normal mucosa of the right semicolon in in track1 [ Time Frame: 10 - 30 months ]
    The pathological assessment of the normal mucosa of the right hemicolon: presence of biofilm, dysplasia and inflammation.

  8. Assessment of the side effects and adverse events regarding to the spraying of the right hemicolon with fosfomycin/metronidazole gel in track1 [ Time Frame: 10 - 30 months ]
    Safety assessment of the spraying of the right hemicolon with fosfomycin/metronidazole gel. This will be assessed through adverse events reported at least 19 days after the intervention (postoperative day 14).

  9. Differences in gene expression in the normal mucosa from preoperative biopsies and the operative biopsies in track 2 [ Time Frame: 10 - 30 months ]
    Differences in gene expression in the normal mucosa from preoperative biopsies and the operative biopsies using the PanCancer IO 360TM Gene Expression Panel (nanoString).

  10. Differences in gene expression in the tumor tissue from the mucosal resection compared with archived FFPE tumor tissue from patients with colon adenoma in track 2 [ Time Frame: 10 - 30 months ]
    Differences in gene expression in the tumor tissue from the mucosal resection compared with archived FFPE tumor tissue from patients with colon adenoma using the PanCancer IO 360TM Gene Expression Panel (nanoString).

  11. Differences in gene expression in the preoperative blood samples and the blood samples taken from patients in track 2 on the operation day [ Time Frame: 10 - 30 months ]
    Differences in gene expression in the preoperative blood samples and the blood samples taken on the operation day using the nCounter® PanCancer Immune Profiling Panel (nanoString).

  12. The pathological assessment of polyp: Occurence of tumor types using the Paris Classification and the Lateral Spreading Tumor Classification. [ Time Frame: 10 - 30 months ]
    The pathological assessment of polyp using the Paris Classification and the Lateral Spreading Tumor Classification to determine tumor type.

  13. The pathological assessment of polyp: size [ Time Frame: 10 - 30 months ]
    The pathological assessment of polyp: size

  14. The immunological assessment of the immunological response [ Time Frame: 10 - 30 months ]
    an assessment of the immunological response via immunoscore

  15. Occurence of biofilm present on the polyp. [ Time Frame: 10 - 30 months ]
    The microbiological assessment of polyp: an assessment of the biofilm present on the polyp. This will be reported as a binary outcome.

  16. The pathological assessment of the normal mucosa of the right hemicolon in track 2 [ Time Frame: 10 - 30 months ]
    The pathological assessment of the normal mucosa of the right hemicolon: presence of biofilm, dysplasia and inflammation.

  17. Assessment of any adverse events or side effects regarding the spraying of the right hemicolon with fosfomycin/metronidazole gel in track 2. [ Time Frame: 10 - 30 months ]
    Assessment of the spraying of the right hemicolon with fosfomycin/metronidazole gel. By collecting reported adverse events at least 19 days after the intervention (postoperative day 14).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Inclusion criteria for track 1 and 2a:

  • Male and female patients above 18 years of age with either:

right-sided colon cancer tumor with adenocarcinoma histologically verified scheduled for open or laparoscopic resection at the Department of Surgery, Herlev Hospital or Zealand University Hospital for track 1.

Right-sided adenomas ≥2cm in diameter endoscopically verified scheduled for endoscopic mucosal resection at the Department of Surgery, Herlev Hospital or Zealand University Hospital for track 2a.

  • ASA I,II or III
  • The caecum must be reached by the endoscope.

Inclusion criteria for retrospective controls (track 2b):

Male and female patients above 18 years of age who were operated for colon adenoma ≥2cm in diameter in the right hemicolon in 2018 at Department of Surgery, Zealand University Hospital. They will be matched 2:1 with the patients included in track 2a (cases) based on age and gender and pathology of the tumor.

Exclusion Criteria:

Exclusion criteria for track 1 and track 2a

  1. Patients with previous allergic reaction to fosfomycin and/or metronidazole
  2. Patients under current antibiotic treatment or patient who had the last dose of antibiotics 30 days prior to inclusion.
  3. Patients with a non-passable tumor or patients where a part of the tumor is not visible during endoscopy (Track 1)
  4. Patients with neoadjuvant chemotherapy or radiation 12 months prior to the resection.
  5. Patients with a history of familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC)
  6. Patients with a history of inflammatory bowel disease (IBD)
  7. Patients under current treatment with warfarin (Marevan) and phenprocoumon (Marcoumar), or NOAK such as dabigatran (Pradaxa®), rivaroxiban (Xarelto®), edoxaban (Lixiana®) or apixaban (Eliquis®)
  8. Patients under current treatment with Fenemal (Phenobarbital)
  9. Patients who are receiving preoperative intravenous treatment with ferric carboxymaltose.
  10. Patients who previously have received a fecal transplantation
  11. Patients who have previously had colorectal cancer, and are now presenting with a secondary colon tumor.
  12. Patients with a current alcohol use disorder (AUD): defined as a patient who are currently drinking 8 or more drinks/week for women and 15 or more drinks/week for men.
  13. Predictable poor compliance (psychiatric disease, not speaking fluent Danish, mentally, impaired etc)
  14. Patients with an American Society of Anaesthesiologists physical status
  15. Classification (ASAscore) of IV.
  16. Patients unable to be sedated
  17. Pregnancy or lactation (fertile women must have a negative serum or urine pregnancy test to participate)
  18. Fertile women who do not use safe contraception during the study period
  19. Following contraceptive methods are acceptable when used consistently and in accordance, with both the product label and the instructions of the physician are:

    • Oral contraceptive, either combined or progestogen alone
    • Injectable progestogen
    • Implants of levonorgestrel
    • Estrogenic vaginal ring
    • Percutaneous contraceptive patches
    • Intrauterine device or intrauterine system with a documented failure rate < 1% per year
    • Male partner sterilization (vasectomy with documented azoospermia) prior to female patient ́s entry into the study, and this male is the sole partner for that patient.
    • Double barrier method: condom with spermicidal agent (foam/gel/film/cream/suppository), condom and occlusive cap (diaphragm or cervical/vault cap) with vaginal spermicidal agent (foam/gel/film/cream/suppository).

Exclusion criteria for retrospective controls (track 2b):

  • Patients under the age of 18 years during the resection for colon adenoma
  • Patients who were under antibiotic treatment during the EMR or patients who had the last dose of antibiotics 30 days prior to EMR
  • Patients with neoadjuvant chemotherapy or radiation 12 months prior to the resection
  • Patients with a history of familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC)
  • Patients with a history of inflammatory bowel disease (IBD)
  • Patients who previously have received a fecal transplantation
  • Patients who have previously had colorectal cancer
  • Patients registered in "Vævsanvendelsesregistret"
  • Patients with insufficient tissue samples

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04312360


Contacts
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Contact: Astrid LB Bennedsen, M.D. +4528529432 aslb@regionsjaelland.dk
Contact: Luyi Cai, BSc. +4530114537 lcai@regionsjaelland.dk

Locations
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Denmark
Department of Surgery, Herlev Hospital Not yet recruiting
Copenhagen, Denmark, 2730
Contact: Peter Vilmann, DMSc, MD         
Department of Surgery, Zealand University Hospital Recruiting
Køge, Denmark, 4200
Contact: Astrid LB Bennedsen, MD         
Sub-Investigator: Hans Raskov, MD.         
Sponsors and Collaborators
Zealand University Hospital
Costerton Biofilm Center
Reponex Pharmaceuticals A/S
Region Zealand
Investigators
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Principal Investigator: Astrid LB Bennedsen, M.D. Department of Surgery, Zealand University Hospital
Principal Investigator: Ismail Gögenur, DMSc, MD, Department of Surgery, Zealand University Hospital
Principal Investigator: Peter Vilmann, DMSc, MD Department of Surgery, Herlev Hospital
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Responsible Party: Zealand University Hospital
ClinicalTrials.gov Identifier: NCT04312360    
Other Study ID Numbers: REG-010-2019
2019-000131-51 ( EudraCT Number )
First Posted: March 18, 2020    Key Record Dates
Last Update Posted: March 26, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Zealand University Hospital:
colon cancer
Endoscopy
endoscopic procedure
bacteria
colon adenoma
microbiota
fosfomycin
metronidazole
biofilm
mucosa
Additional relevant MeSH terms:
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Colonic Neoplasms
Adenoma
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Metronidazole
Fosfomycin
Anti-Infective Agents
Anti-Bacterial Agents
Antiprotozoal Agents
Antiparasitic Agents