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    Clinical Trial Results:
    Perioperative metformin treatment for colon cancer - a randomized trial

    Summary
    EudraCT number
    		 2017-000722-35
    Trial protocol
    		 DK  
    Global end of trial date
    08 Oct 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jun 2024
    First version publication date
    13 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ECO-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03359681
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ismail Gögenur
    Sponsor organisation address
    Fælledvej 11, Slagelse, Denmark,
    Public contact
    Department of surgery, Department of surgery Slagelse Hospital, 45 61335122, eco@regionsjaelland.dk
    Scientific contact
    Department of surgery, Department of surgery Slagelse Hospital, 45 61335122, eco@regionsjaelland.dk
    Sponsor organisation name
    Ismail Gögenur
    Sponsor organisation address
    Lykkebækvej 1, Køge, Denmark, 4600
    Public contact
    Ismail Gögenur, Ismail Gögenur, +45 26336426, igo@regionsjaelland.dk
    Scientific contact
    Ismail Gögenur, Ismail Gögenur, +45 26336426, igo@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
    01 Aug 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Oct 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the study is to investigate the effect of treatment with metformin on cell proliferation and on metabolic and immunological changes in non-diabetic patients with colon cancer. The primary outcome is determination of the difference of the level of proliferation after the intervention (time of surgery) adjusted for the level seen at baseline (time of colonoscopy). Another primary outcome is the difference in tumorinfiltrating CD3 and CD8 positive lymphocytes after the intervention adjusted for the level seen at baseline.
    Protection of trial subjects
    Study medication was added as an extra treatment to existing standard of care
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2018
    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: 59
    Worldwide total number of subjects
    59
    EEA total number of subjects
    59
    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)
    15
    From 65 to 84 years
    43
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 59 patients were included and randomized. Of these 11 left the trial before surgery and were thus not included in the analyses (no data available). Out of the 11, four never received study medication. The seven patients that did receive study medication were included in the report of adverse events.

    Pre-assignment
    Screening details
    		 The lists for all multidisciplinary team conferences were screened for eligible patients

    Period 1
    Period 1 title
    Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 metformin
    Arm description
    		 metformin treatment 500mg three times a day
    Arm type
    		 Experimental

    Investigational medicinal product name
    metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    First two days with 500mg once a day, then two days with 500mg twice a day and finally 500mg three times ad day. Patients were treatetd for 20 days before surgery and 10 days after.

    Arm title
    		 Placebo
    Arm description
    		 placebo capsules looking identical to the ones in the metformin arm
    Arm type
    		 Placebo

    Investigational medicinal product name
    metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    500mg three times a day

    Investigational medicinal product name
    metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    500mg three times a day

    Number of subjects in period 1 [1]
    		metformin Placebo
    Started
    28
    27
    surgery
    23
    25
    Completed
    22
    25
    Not completed
    6
    2
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    5
    -
         Surgery cancelled
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: four patients were randomized but never received the intervention - one because of reduced kidney function and three because they withdrew consent to participate before starting the medication

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    metformin
    Reporting group description
    		 metformin treatment 500mg three times a day

    Reporting group title
    Placebo
    Reporting group description
    		 placebo capsules looking identical to the ones in the metformin arm

    Reporting group values
    		 metformin Placebo Total
    Number of subjects
    		 28 27 55
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age is reported for the 48 patients that completed the trial at least until surgery and so were included in the analyses of outcomes
    Units: years
        arithmetic mean (standard deviation)
    		 66.5 ( 7.9 ) 69.7 ( 10.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 15 31
        Male
    		 12 12 24

    End points

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    End points reporting groups
    Reporting group title
    metformin
    Reporting group description
    		 metformin treatment 500mg three times a day

    Reporting group title
    Placebo
    Reporting group description
    		 placebo capsules looking identical to the ones in the metformin arm

    Primary: CD3 lymphocytes in tumor

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    End point title
    		 CD3 lymphocytes in tumor
    End point description
    Tumor cells were classified as positive or negative for CD3 within an area of interest and the density of positive nuclei was calculated. The difference from before treatment to after treatment was compared between the two groups
    End point type
    Primary
    End point timeframe
    before and after treatment with metformin or placebo
    End point values
    		 metformin Placebo
    Number of subjects analysed
    22
    23
    Units: cells per area of interest
        median (inter-quartile range (Q1-Q3))
    -153.1 (-355.7 to 133.2)
    -58.96 (-342.05 to 85.61)
    Statistical analysis title
    		 CD3 lymphocytes in tumor
    Comparison groups
    metformin v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.98
    Method
    		 Willcoxon rank sum
    Confidence interval

    Primary: CD8 lymphocytes in tumor

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    End point title
    		 CD8 lymphocytes in tumor
    End point description
    Tumor cells were classified as positive or negative for C83 within an area of interest and the density of positive nuclei was calculated. The difference from before treatment to after treatment was compared between the two groups
    End point type
    Primary
    End point timeframe
    Before and after treatment with metformin or placebo
    End point values
    		 metformin Placebo
    Number of subjects analysed
    22
    23
    Units: cells
        median (inter-quartile range (Q1-Q3))
    -108.1 (-189.89 to -8.15)
    -16.34 (-142.61 to 46.68)
    Statistical analysis title
    		 CD8 lymphocytes in tumor
    Comparison groups
    metformin v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.36
    Method
    		 Willcoxon rank sum
    Confidence interval

    Secondary: Blood glucose above 10mmol/l

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    End point title
    		 Blood glucose above 10mmol/l
    End point description
    End point type
    Secondary
    End point timeframe
    The number of patients with at least one glucose measurement above 10.0mmol/l within the first two days after surgery
    End point values
    		 metformin Placebo
    Number of subjects analysed
    23 [1]
    25 [2]
    Units: people
    5
    13
    Notes
    [1] - 5 patients left the study before surgery
    [2] - 2 patients left the study before surgery
    Statistical analysis title
    		 Blood glucose above 10.0mmol/l
    Comparison groups
    metformin v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.04
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from the day the patients started taking the study medication until 24 hours after last ingestion of study medication
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    0
    Reporting groups
    Reporting group title
    metformin
    Reporting group description
    		 metformin treatment 500mg three times a day

    Reporting group title
    Placebo
    Reporting group description
    		 placebo capsules looking identical to the ones in the metformin arm

    Serious adverse events
    		 metformin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 28 (21.43%)
    4 / 27 (14.81%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Cardiac arrest
    Additional description: at home before surgery, experienced chest discomfort in the evening and was found dead in her bed the next morning
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Perforated ulcer
    Additional description: perforated ulcer after colon resection leading to surgery and prolonged length of stay
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic leak
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
    Additional description: wound opened bedside and later resutured under general anaesthesia. Prolonged length of stay
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colon perforation
    Additional description: readmitted after colonoscopy med removal og polyp with perforation. Treated with antibiotics.
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rectal bleeding
    Additional description: readmitted after surgery with rectal bleeding. Bleeding stopped spontaneously with no need of interventions or blood transfusions
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
    Additional description: abdominal pain and elevated inflammatory markers after surgery. Diagnostic laparoscopy with ileus but no other signs of complications. Prolonged length of stay due to this.
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
    Additional description: reoperated
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
    Additional description: readmitted due to vominting after surgery
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
    Additional description: leading to readmission
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 27 (3.70%)
         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: 4%
    Non-serious adverse events
    		 metformin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 28 (85.71%)
    22 / 27 (81.48%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    edema
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Vomiting or nausea
         subjects affected / exposed
    9 / 28 (32.14%)
    3 / 27 (11.11%)
         occurrences all number
    13
    3
    Abdominal pain
         subjects affected / exposed
    6 / 28 (21.43%)
    8 / 27 (29.63%)
         occurrences all number
    10
    11
    change in bowel movements
         subjects affected / exposed
    10 / 28 (35.71%)
    6 / 27 (22.22%)
         occurrences all number
    13
    8
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Pneumonia
    Additional description: not leading to readmission or prolonged length of stay
         subjects affected / exposed
    3 / 28 (10.71%)
    3 / 27 (11.11%)
         occurrences all number
    3
    3
    Candida infection
    Additional description: oral
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 27 (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
    17 Jun 2021
    CD3 and CD8 were added as primary outcomes instead of secundary outcomes

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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