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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2019-000131-51
    Trial protocol
    		 DK  
    Global end of trial date
    01 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2024
    First version publication date
    18 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1921
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04312360
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Research Ethics Committee number: 66694
    Sponsors
    Sponsor organisation name
    Zealand University Hospital
    Sponsor organisation address
    Lykkebækvej 1, Køge, Denmark, 4600
    Public contact
    Zealand University Hospital, Zealand University Hospital, +45 28526432, aslb@regionsjaelland.dk
    Scientific contact
    Zealand University Hospital, Zealand University Hospital, +45 28526432, aslb@regionsjaelland.dk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Jun 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jul 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    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.
    Protection of trial subjects
    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.
    Background therapy
    		 All patients included in this trial received a bowel preparation by PicoPrep before the intervention colonoscopies. All patients in track 1 received perioperative administration of 500mg of metronidazole during the colon cancer surgery (post-trial-intervention). All patient in track 2 received a bowel preparation by PicoPrep before the endosckopic mucosal resection (post-trial-intervention).
    Evidence for comparator
    		 For comparators, we will compare tissue and blood samples at baseline with samples after the invervention. The surgical resection of colon adenomas are usually performed as an endoscopic mucosal resection (EMR). This is a delicate procedure to perform as only the superficial layers of the colon is affected, but the patients avoid surgical incisions of the abdominal wall. Biopsies are not taken before EMR procedures as the inflammation and scaring of the tissue may make the EMR impossible to perform. In order to have precursor tissue that has not been treated with the antibiotic intervention we will have a retrospective cohort of 28 patients with colon precursor lesions (track 2b). We will retrieve FFPE tissue from the resected mucosa bearing adenoma. They will have had endoscopic mucosal resection performed in 2018 at Department of Surgery, Zealand University Hospital.
    Actual start date of recruitment
    17 Jan 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    4
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment at the Surgical Department, Zealand University Hospita was from January 2020 until April 2022. Recruitment at the Gastro Unit, Herlev Hospital, was from September 2020 until April 2022.

    Pre-assignment
    Screening details
    		 Consecutive patients with endoscopically diagnosed right-sided colon adenomas/precursor lesions (≥2cm in diameter) or right-sided colon cancer tumors were eligible for inclusion in the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Experimental
    Arm description
    		 Therapeutic endoscopy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fosfomycin
    Investigational medicinal product code
    J01 XX 01
    Other name
    Fosfomycin disodium, Infectofos
    Pharmaceutical forms
    Powder and gel for gel
    Routes of administration
    Local use
    Dosage and administration details
    During the therapeutic endoscopy the right hemicolon was sprayed with 100ml of the gel (8mg/ml of fosfomycin), yielding a dose of 800mg of fosfomycin. For this study, the following dosages was chosen: 800mg of fosfomycin and 200mg of metronidazole in 100ml of gel. We estimated that this dosage of gel is sufficient to cover the inner surface of the right hemicolon. The gel consisted of two components. One component consisted of fosfomycin, metronidazole and a solution. The other component was a gel. During administration, the two components were delivered through a dual channel colono-videoscope. The gel formed on the bowel wall and adhered to the mucosa. This was a one-time application at least five days before the surgical tumour resection.

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    J01 XD 01
    Other name
    metronidazole “B. Braun”
    Pharmaceutical forms
    Powder and gel for gel
    Routes of administration
    Local use
    Dosage and administration details
    During the therapeutic endoscopy the right hemicolon was sprayed with 100ml of the gel (2mg/ml of metronidazole), yielding a dose of 200mg of metronidazole. For this study, the following dosages was chosen: 800mg of fosfomycin and 200mg of metronidazole in 100ml of gel. We estimated that this dosage of gel is sufficient to cover the inner surface of the right hemicolon. The gel consisted of two components. One component consisted of fosfomycin, metronidazole and a solution. The other component was a gel. During administration, the two components were delivered through a dual channel colono-videoscope. The gel formed on the bowel wall and adhered to the mucosa. This was a one-time application at least five days before the surgical tumour resection.

    Number of subjects in period 1
    		Experimental
    Started
    28
    Completed
    22
    Not completed
    6
         Consent withdrawn by subject
    5
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 28 28
    Age categorical
    Age at inclusion
    Units: Subjects
        Adults (18-64 years)
    		 4 4
        From 65-84 years
    		 24 24
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 11 11
    Subject analysis sets

    Subject analysis set title
    Track 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with colon cancer

    Subject analysis set title
    Track 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with colon adenoma/precursor lesion

    Subject analysis set title
    Track 1 post-intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Same patients as track 1, post-intervention samples

    Subject analysis set title
    Track 2 post-intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Same patients as track 2, post-intervention samples

    Subject analysis set title
    Track 2b retrospective controls
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Each patient from track 2 was matched by age and gender with two historical controls (track 2b) with an EMR procedure in 2018, in order to obtain neoplastic tissue samples that were not exposed to the antibiotics.

    Subject analysis sets values
    		 Track 1 Track 2 Track 1 post-intervention Track 2 post-intervention Track 2b retrospective controls
    Number of subjects
    14
    14
    14
    14
    24
    Age categorical
    Age at inclusion
    Units: Subjects
        Adults (18-64 years)
    2
    2
    2
    2
        From 65-84 years
    12
    12
    12
    12
        85 years and over
    0
    0
    0
    0
    Age continuous
    Age at inclusion
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    9
    8
    9
    8
        Male
    5
    6
    5
    6

    End points

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    End points reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 Therapeutic endoscopy

    Subject analysis set title
    Track 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with colon cancer

    Subject analysis set title
    Track 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with colon adenoma/precursor lesion

    Subject analysis set title
    Track 1 post-intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Same patients as track 1, post-intervention samples

    Subject analysis set title
    Track 2 post-intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Same patients as track 2, post-intervention samples

    Subject analysis set title
    Track 2b retrospective controls
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Each patient from track 2 was matched by age and gender with two historical controls (track 2b) with an EMR procedure in 2018, in order to obtain neoplastic tissue samples that were not exposed to the antibiotics.

    Primary: Change in bacterial biomass (non-tumour bearing mucosa)

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    End point title
    		 Change in bacterial biomass (non-tumour bearing mucosa)
    End point description
    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 background tissue biomass volume was used to adjust the bacterial biomass volume. The specific measurement variable is 3D biofilm mass. The method of aggregation will be means.
    End point type
    Primary
    End point timeframe
    Baseline to surgical tumour resection
    End point values
    		 Track 1 Track 2 Track 1 post-intervention Track 2 post-intervention
    Number of subjects analysed
    9 [1]
    10 [2]
    9 [3]
    10 [4]
    Units: Percentage
        number (not applicable)
    9
    10
    9
    10
    Notes
    [1] - 4 patients dropped out. One patient was excluded for analyses due to staining artefacts.
    [2] - 1 pt dropped out. 1 pt was a screening failure. 2 patients exluded: artefacts and no post-tissue.
    [3] - 4 patients dropped out. One patient was excluded for analyses due to staining artefacts.
    [4] - 1 pt dropped out. 1 pt was a screening failure. 2 patients exluded: artefacts and no post-tissue.
    Statistical analysis title
    		 Change in bacterial biomass (track 1)
    Statistical analysis description
    Percentage bacterial biomass (mean (range)): Baseline: 5.390e-03 (2.997e-05 – 2.050e-02) Post-intervention: 6.081e-04 (8.465e-04 – 1.151e-02)
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.674 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference in bacterial biomass
    Confidence interval
    Notes
    [5] - Paired one-tailed wilcoxon test
    Statistical analysis title
    		 Change in bacterial biomass (track 2)
    Statistical analysis description
    Percentage bacterial biomass (mean (range)): Baseline: 3.0e-04 (2.1e-05 - 7.4e-04) Post-intervention: 9.8e-05 (3.3e-06 – 2.4e-04)
    Comparison groups
    Track 2 v Track 2 post-intervention
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.025 [6]
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference in bacterial biomass
    Confidence interval
    Notes
    [6] - Paired one-tailed t-test

    Primary: Change in gene expression (non-tumour bearing mucosa)

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    End point title
    		 Change in gene expression (non-tumour bearing mucosa)
    End point description
    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, and markers of the microenvironment and the immune response. The analyses will be performed using the PanCancer IO 360TM Gene Expression Panel (nanoString).
    End point type
    Primary
    End point timeframe
    Baseline to surgical tumour resection
    End point values
    		 Track 1 Track 2 Track 1 post-intervention Track 2 post-intervention
    Number of subjects analysed
    10 [7]
    11 [8]
    10 [9]
    11 [10]
    Units: log2 Fold Change
        number (not applicable)
    10
    11
    10
    11
    Notes
    [7] - 4 patients dropped out before the intervention
    [8] - 1 patient dropped out. 1 patient was a screening failure. 1 patient had no post-intervention tissue
    [9] - 4 patients dropped out before the intervention
    [10] - 1 patient dropped out. 1 patient was a screening failure. 1 patient had no post-intervention tissue
    Statistical analysis title
    		 Differentially expressed genes (track 1)
    Statistical analysis description
    Differentially expressed genes in the non-tumour bearing mucosa samples after the intervention using the Wald significance test with an adjusted p-value <0.05 using the Benjamini-Hochberg approach: we observed one gene down-regulated and 27 genes up-regulated.
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wald significance test
    Parameter type
    		 log2FoldChange
    Confidence interval
    Statistical analysis title
    		 Differentially expressed genes (track 2)
    Statistical analysis description
    Non-tumour bearing mucosa samples before and after the antibiotic application were compared for differentially expressed (DE) genes using the Wald significance test with an adjusted p-value <0.05 using the Benjamini-Hochberg approach one gene was found to be downregulated, however, this is likely an effect of the multiple testing due to the nearly uniform distribution of the p-value histogram.
    Comparison groups
    Track 2 v Track 2 post-intervention
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wald significance test
    Parameter type
    		 log2FoldChange
    Confidence interval

    Primary: Change in bacterial composition (non tumour bearing)

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    End point title
    		 Change in bacterial composition (non tumour bearing)
    End point description
    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.
    End point type
    Primary
    End point timeframe
    Baseline to surgical tumour resection
    End point values
    		 Track 1 Track 2 Track 1 post-intervention Track 2 post-intervention
    Number of subjects analysed
    10 [11]
    12 [12]
    10 [13]
    12 [14]
    Units: R2 (proportion)
        number (not applicable)
    10
    12
    10
    12
    Notes
    [11] - 4 patients dropped out before the intervention
    [12] - 1 patient dropped out before the intervention. 1 patient was a screening failure
    [13] - 4 patients dropped out before the intervention
    [14] - 1 patient dropped out before the intervention. 1 patient was a screening failure
    Statistical analysis title
    		 Beta diversity (track 1)
    Statistical analysis description
    The beta diversity was compared between pre- and post-samples using the PERMANOVA test: R2=13%, F=2.3, p=0.002.
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.002
    Method
    		 PERMANOVA
    Confidence interval
    Statistical analysis title
    		 Beta diversity (track 2)
    Statistical analysis description
    The beta diversity was compared between pre- and post-samples using the PERMANOVA test: R2=11%, F=2.1, p=0.021.
    Comparison groups
    Track 2 v Track 2 post-intervention
    Number of subjects included in analysis
    24
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.021
    Method
    		 PERMANOVA
    Confidence interval
    Statistical analysis title
    		 Bacterial presence (Track 1)
    Statistical analysis description
    Tissue slides pre- and post-intervention were manually evaluated for the presence of Bacteroides fragilis, Fusobacterium. *Bacteroides fragilis (N (%)): Baseline: 10 (100) Post-intervention: 10 (100) *Fusobacterium (N (%)): Baseline: 8 (80) Post-intervention: 7 (70)
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1 [15]
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [15] - McNemar's Chi-squared test with continuity correction.
    Statistical analysis title
    		 Bacterial presence (Track 2)
    Statistical analysis description
    Tissue slides pre- and post-intervention were manually evaluated for the presence of Bacteroides fragilis, Fusobacterium. *Bacteroides fragilis (N (%)): Baseline: 8 (66.7) Post-intervention: 9 (81.8) *Fusobacterium (N (%)): Baseline: 7 (58.3) Post-intervention: 7 (64.6)
    Comparison groups
    Track 2 v Track 2 post-intervention
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≥ 0.64 [16]
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [16] - McNemar's Chi-squared test with continuity correction

    Primary: Change in bacterial biomass (tumour centre)

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    End point title
    		 Change in bacterial biomass (tumour centre)
    End point description
    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 background tissue biomass volume was used to adjust the bacterial biomass volume. The specific measurement variable is 3D biofilm mass. The method of aggregation will be means.
    End point type
    Primary
    End point timeframe
    Baseline to surgical tumour resection.
    End point values
    		 Track 1 Track 1 post-intervention
    Number of subjects analysed
    9 [17]
    9 [18]
    Units: Percent
        number (not applicable)
    9
    9
    Notes
    [17] - Four patients dropped out before the intervention. One patient had no tumour centre tissue available
    [18] - Four patients dropped out before the intervention. One patient had no tumour centre tissue available
    Statistical analysis title
    		 Change in bacterial biomass (tumour centre)
    Statistical analysis description
    Percentage of bacterial biomass (mean (range)): Baseline: 9.216e-03 (4.4e-4 – 1.0) Post-intervention: 7.453e-02 (1.3e-5 – 0.4)
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.5 [19]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [19] - Paired one-tailed wilcoxon

    Primary: Change in bacterial biomass (tumour periphery)

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    End point title
    		 Change in bacterial biomass (tumour periphery)
    End point description
    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 background tissue biomass volume was used to adjust the bacterial biomass volume. The specific measurement variable is 3D biofilm mass. The method of aggregation will be means.
    End point type
    Primary
    End point timeframe
    Baseline to surgical tumour resection
    End point values
    		 Track 1 Track 1 post-intervention
    Number of subjects analysed
    10 [20]
    10 [21]
    Units: percent
        number (not applicable)
    10
    10
    Notes
    [20] - 4 patients dropped out before the intervention.
    [21] - 4 patients dropped out before the intervention.
    Statistical analysis title
    		 Change in bacterial biomass (tumour periphery)
    Statistical analysis description
    Percentage of bacterial biomass (mean (range)): Baseline: 0.1 (9.8e-5 – 0.6) Post-intervention: 1.1e-02 (8.0e-04 – 4.2e-2)
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.161 [22]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [22] - Paired one-tailed wilcoxon test

    Primary: Change in bacterial biomass (adenoma)

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    End point title
    		 Change in bacterial biomass (adenoma)
    End point description
    Bacterial biomass of the adenoma tissue after the surgical tumour resection from patients who received the intervention was compared with bacterial biomass of adenoma tissue in a retrospective cohort of patients. 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 background tissue biomass volume was used to adjust the bacterial biomass volume. The specific measurement variable is 3D biofilm mass. The method of aggregation will be means.
    End point type
    Primary
    End point timeframe
    Retrospective control group and adenomas from patients who received the intervention after surgical tumour resection
    End point values
    		 Track 2 Track 2b retrospective controls
    Number of subjects analysed
    12 [23]
    22 [24]
    Units: percent
        number (not applicable)
    12
    22
    Notes
    [23] - 2 patients excluded (tissue unavailable+artefact).
    [24] - 2 controls were excluded due to staining artefacts and size of neoplasms
    Statistical analysis title
    		 Change in bacterial biomass (adenoma)
    Statistical analysis description
    Percentage of bacterial biomass (mean (range)): Control-group: 8.6e-03 (1.1e-05 - 7.5e-02) Post-intervention, case-group: 1.1e-02 (3.4e-04 - 5.5e-02)
    Comparison groups
    Track 2 v Track 2b retrospective controls
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.386 [25]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [25] - One-tailed mann-whitney u test

    Primary: Change in bacterial composition (tumour centre)

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    End point title
    		 Change in bacterial composition (tumour centre)
    End point description
    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.
    End point type
    Primary
    End point timeframe
    Baseline to surgical tumour resection.
    End point values
    		 Track 1 Track 1 post-intervention
    Number of subjects analysed
    10 [26]
    10 [27]
    Units: R2 (proportion)
        number (not applicable)
    10
    10
    Notes
    [26] - 4 patients dropped out before the intervention
    [27] - 4 patients dropped out before the intervention
    Statistical analysis title
    		 Beta diversity
    Statistical analysis description
    The beta diversity was compared between pre- and post-samples using the PERMANOVA test: R2=14%, F=2.5, p=0.006.
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.006
    Method
    		 PERMANOVA
    Confidence interval
    Statistical analysis title
    		 Bacterial presence
    Statistical analysis description
    Tissue slides pre- and post-intervention were manually evaluated for the presence of Bacteroides. fragilis, Fusobacterium. *Bacteroides fragilis (N (%)): Baseline: 9 (90) Post-intervention: 8 (89) *Fusobacterium (N (%)): Baseline: 7 (70) Post-intervention: 7 (78)
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1 [28]
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [28] - McNemar's Chi-squared test with continuity correction

    Primary: Change in bacterial composition (tumour periphery)

    		 Close Top of page
    End point title
    		 Change in bacterial composition (tumour periphery)
    End point description
    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.
    End point type
    Primary
    End point timeframe
    Baseline to surgical tumour resection
    End point values
    		 Track 1 Track 1 post-intervention
    Number of subjects analysed
    10 [29]
    10 [30]
    Units: R2 (proportion)
        number (not applicable)
    10
    10
    Notes
    [29] - 4 patients dropped out before the intervention
    [30] - 4 patients dropped out before the intervention
    Statistical analysis title
    		 Beta diversity
    Statistical analysis description
    The beta diversity was compared between pre- and post-samples using a PERMANOVA test: R2=15%, F=3.0, p=0.004 for the tumour periphery
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.004
    Method
    		 PERMANOVA
    Confidence interval
    Statistical analysis title
    		 Bacterial presence
    Statistical analysis description
    Tissue slides pre- and post-intervention were manually evaluated for the presence of Bacteroides fragilis, Fusobacterium. *Bacteroides fragilis (N (%)): Baseline: 10 (100) Post-intervention: 10 (100) *Fusobacterium (N (%)): Baseline: 9 (90) Post-intervention: 10 (100)
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1 [31]
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [31] - McNemar's Chi-squared test with continuity correction

    Primary: Change in gene expression (tumour centre)

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    End point title
    		 Change in gene expression (tumour centre)
    End point description
    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, and markers of the microenvironment and the immune response. The analyses will be performed using the PanCancer IO 360TM Gene Expression Panel (nanoString).
    End point type
    Primary
    End point timeframe
    Baseline to surgical tumour resection
    End point values
    		 Track 1 Track 1 post-intervention
    Number of subjects analysed
    7 [32]
    7 [33]
    Units: Log2fold change
        number (not applicable)
    7
    7
    Notes
    [32] - 4 patients dropped out. 3 patients were excluded due to no post-intervention samples.
    [33] - 4 patients dropped out. 3 patients were excluded due to no post-intervention samples.
    Statistical analysis title
    		 Differentially expressed genes
    Statistical analysis description
    Tumour centre samples before and after the antibiotic application were compared for differentially expressed (DE) genes using the Wald significance test with a log2 fold change ≥0.5 and an adjusted p-value <0.05 using the Benjamini-Hochberg approach: six genes were down-regulated and one gene was upregulated.
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    14
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wald significance test
    Parameter type
    		 log2FoldChange
    Confidence interval

    Primary: Change in gene expression (tumour periphery)

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    End point title
    		 Change in gene expression (tumour periphery)
    End point description
    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, and markers of the microenvironment and the immune response. The analyses will be performed using the PanCancer IO 360TM Gene Expression Panel (nanoString).
    End point type
    Primary
    End point timeframe
    Baseline to surgical tumour resection
    End point values
    		 Track 1 Track 1 post-intervention
    Number of subjects analysed
    10 [34]
    10 [35]
    Units: Log2foldchange
        number (not applicable)
    10
    10
    Notes
    [34] - 4 patients dropped out before the intervention
    [35] - 4 patients dropped out before the intervention
    Statistical analysis title
    		 Differentially expressed genes
    Statistical analysis description
    Tumour periphery samples before and after the antibiotic application were compared for differentially expressed (DE) genes using the Wald significance test with an adjusted p-value <0.05 using the Benjamini-Hochberg approach: 12 genes were down-regulated and 10 genes were up-regulated.
    Comparison groups
    Track 1 v Track 1 post-intervention
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wald significance test
    Parameter type
    		 log2FoldChange
    Confidence interval

    Primary: Change in gene expression (adenomas)

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    End point title
    		 Change in gene expression (adenomas)
    End point description
    Gene expression of the adenoma tissue after the surgical tumour resection from patients who received the intervention was compared with gene expression of adenoma tissue in a retrospective cohort of patients.
    End point type
    Primary
    End point timeframe
    Retrospective control group and adenomas from patients who received the intervention after surgical tumour resection
    End point values
    		 Track 2 Track 2b retrospective controls
    Number of subjects analysed
    12 [36]
    21 [37]
    Units: Log2foldchange
        number (not applicable)
    12
    21
    Notes
    [36] - 1 pt dropped out, 1 patient was screening failure.
    [37] - 1 control removed due to tumor size, 2 controls removed due to very low gene count.
    Statistical analysis title
    		 Differentially expressed genes
    Statistical analysis description
    DE genes between pre- and post-intervention samples (time A vs B) were analysed using the Wald significance test with adjustment for multiple testing by the Benjamini-Hochberg approach: three genes down-regulated and seven genes up-regulated.
    Comparison groups
    Track 2 v Track 2b retrospective controls
    Number of subjects included in analysis
    33
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wald significance test
    Parameter type
    		 log2FoldChange
    Confidence interval

    Primary: Change in bacterial composition (adenomas)

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    End point title
    		 Change in bacterial composition (adenomas)
    End point description
    End point type
    Primary
    End point timeframe
    Retrospective control group and adenomas from patients who received the intervention after surgical tumour resection
    End point values
    		 Track 2 Track 2b retrospective controls
    Number of subjects analysed
    12
    24
    Units: Numbers
    12
    24
    Statistical analysis title
    		 Bacterial presence
    Statistical analysis description
    Tissue slides from control group patients (not exposed for antibiotics) and post-intervention tissue slides were manually evaluated for the presence of Bacteroides fragilis, Fusobacterium. *Bacteroides fragilis (N (%)): Control group: 22 (92) Post-intervention: 10 (83) *Fusobacterium (N (%)): Control group: 13 (54) Post-intervention: 8 (67)
    Comparison groups
    Track 2 v Track 2b retrospective controls
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≥ 0.588 [38]
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [38] - Test for Bacteroides fragilis p=0.588. Test for Fusobacterium p=0.721. McNemar's Chi-squared test with continuity correction.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the day of intervention (therapeutic endoscopy) until 14 days postoperatively (at least 19 days after the intervention) and then 12 months postoperatively'
    Adverse event reporting additional description
    CTCAE v5
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Track 1
    Reporting group description
    		 Patients with colon cancer

    Reporting group title
    Track 2
    Reporting group description
    		 Patients with colon adenoma/precursor lesion

    Serious adverse events
    		 Track 1 Track 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Fever after a surgical procedure leading to readmission
    Additional description: One patient had a SAE grade 3: the patient developed fever in the hours after the surgical tumour resection, and had to be readmitted to hospital.
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Track 1 Track 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    13 / 13 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoma recurrence
    Additional description: Patients reporting adenoma recurrence within 12 months postoperatively
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Nervous system disorders
    Interrupted sleep
    Additional description: Patients reporting interrupted sleep within 14 days postoperatively
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Fatigue
    Additional description: Patients reporting fatigue within 14 days postoperatively
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Patients experiencing anaemia within 14 days postoperatively
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Light sensitivity
    Additional description: Patients reporting light sensitivity within 14 days postoperatively
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Loose stools
    Additional description: Patients reporting stools with a more loose consistency than before the intervention within 14 days postoperatively
         subjects affected / exposed
    4 / 10 (40.00%)
    10 / 13 (76.92%)
         occurrences all number
    4
    10
    Diarrhoea
    Additional description: Patients reporting diarrhoea within 14 days postoperatively
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 13 (30.77%)
         occurrences all number
    0
    4
    Constipated diarrhoea
    Additional description: Patients who reported constipated diarrhoea within 14 days postoperatively
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Constipation
    Additional description: Patients who reported constipation within 14 days postoperatively
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Abdominal pain
    Additional description: Patients reporting abdominal pain within 14 days postoperatively
         subjects affected / exposed
    4 / 10 (40.00%)
    5 / 13 (38.46%)
         occurrences all number
    4
    5
    Dysgeusia
    Additional description: Patients who reported dysgeusia within 14 days postoperativelly
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Dry mouth
    Additional description: Patients reporting dry mouth within 14 days postoperatively
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Rectal bleeding
    Additional description: Patients reporting rectal bleeding within 14 days postoperatively
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    Arterial bleeding during the endoscopic mucosal resection
    Additional description: Patients developing arterial bleeding during the endoscopic mucosal resection (only track 2)
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Change in stool odour
    Additional description: Patients reporting change in stool odour within 14 days postoperatively
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Yellow coloured stool
    Additional description: Patients reporting yellow coloured stool within 14 days postoperatively
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Faecal incontinence
    Additional description: Patients reporting faecal incontinence within 12 months postoperatively
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Nausea
    Additional description: Patients reporting nausea within 14 days postoperatively
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    Skin and subcutaneous tissue disorders
    Hot flashes
    Additional description: Patients reporting hot flashes within 14 days postoperatively
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
    Additional description: Patients reporting myalgia within 14 days postoperatively
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Weight loss 1-2 kg
    Additional description: Patients reporting weight loss of 1-2 kg within 14 days postoperatively
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Fever
    Additional description: Patients reporting fever within 14 days postoperatively
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    CRP elevation
    Additional description: Patients experiencing CRP elevation within 14 days postoperatively
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2019
    Addition of the exclusion criteria "fenemal usage".
    02 Jul 2020
    Change in PI
    22 Oct 2020
    Removal of the exclusion criteria "preoperative iron infusion" Prolonged study period.
    22 Sep 2022
    An update of the known side-effects of Fosfomycin and Metronidazole was written in the patient information. Change in PI
    05 Jan 2023
    Change in PI

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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