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    Clinical Trial Results:
    Pre-surgical metformin for women with endometrial cancer: a randomised placebo controlled trial

    Summary
    EudraCT number
    		 2014-000991-25
    Trial protocol
    		 GB  
    Global end of trial date
    02 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Feb 2020
    First version publication date
    09 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    R03572
    Additional study identifiers
    ISRCTN number
    		 ISRCTN88589234
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Manchester University NHS Foundation Trust
    Sponsor organisation address
    Oxford Road, Manchester, United Kingdom, M13 9WL
    Public contact
    MFT Research Office, Manchester University NHS Foundation Trust, +44 01612763565, lynne.webster@mft.nhs.uk
    Scientific contact
    MFT Research Office, Manchester University NHS Foundation Trust, +44 01612763565, lynne.webster@mft.nhs.uk
    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
    02 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether metformin has a biological effect on endometrial cancer.
    Protection of trial subjects
    Metformin is generally regarded to be safe and is usually well tolerated, patients will be closely monitoring whilst they are taking the IMP. This involvde careful review of the patient's medical history and blood results prior to recruitment, provision of contact information to allow the patient to discuss any problems, side effects or safety concerns whilst taking the drug, a telephone call after a few days and again after one to two weeks of commencing treatment with metformin or placebo to check for adverse events and careful questioning of the patient at the end of the study to enquire about difficulties encountered whilst taking metformin. To improve tolerability, compliance with the study and reduce side effects, we will ask patients to take one 850mg metformin tablet or placebo for the first three days, and increase to two tablets thereafter. Patients who are unable to tolerate treatment with metformin, or who experience serious adverse events whilst taking it will be advised to discontinue treatment. Patients who have specific contraindications to metformin treatment will not be included in the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2014
    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
    United Kingdom: 93
    Worldwide total number of subjects
    93
    EEA total number of subjects
    93
    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)
    46
    From 65 to 84 years
    46
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from 4 centres around Greater Manchester - Christie, Penine Acute, Tameside and Wrightington, Wigan and Leigh.

    Pre-assignment
    Screening details
    		 Following written informed consent and before commencing treatment with metformin or placebo, the following assessments will be conducted and samples taken: � Medical history (to exclude diabetes on treatment, current metformin treatment, severe renal or liver impairment, drug allergy) � Height and weight (to calculate BMI) � Waist and hip

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Randomisation was provided by Manchester CTU and all information was kept securely within the CTU. Treatment allocation was not made public to investigators or subjects during the trial. Pharmacy had access to an unblinding list in case of emergency unblinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Metformin
    Arm description
    		 Treatment A –Therapeutic arm Metformin 850mg once a day for 3 days, then twice a day until surgery (between 1 and 5 weeks)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin 850mg once a day for 3 days, then twice a day until surgery (between 1 and 5 weeks)

    Arm title
    		 Placebo
    Arm description
    		 Treatment B – Control arm Placebo tablet once a day for 3 days, then twice a day until surgery (between 1 and 5 weeks)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet once a day for 3 days, then twice a day until surgery (between 1 and 5 weeks)

    Number of subjects in period 1
    		Metformin Placebo
    Started
    47
    46
    Completed
    45
    43
    Not completed
    2
    3
         Withdrew prior to recieving trial drug
    2
    -
         Withdrew prior to receiving study drug
    -
    2
         Surgery postponed
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 Treatment A –Therapeutic arm Metformin 850mg once a day for 3 days, then twice a day until surgery (between 1 and 5 weeks)

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment B – Control arm Placebo tablet once a day for 3 days, then twice a day until surgery (between 1 and 5 weeks)

    Reporting group values
    		 Metformin Placebo Total
    Number of subjects
    		 47 46 93
    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
    Units: years
        median (full range (min-max))
    		 64.0 (29.6 to 83.7) 67.1 (39.8 to 85.2) -
    Gender categorical
    Units: Subjects
        Female
    		 47 46 93
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 Treatment A –Therapeutic arm Metformin 850mg once a day for 3 days, then twice a day until surgery (between 1 and 5 weeks)

    Reporting group title
    Placebo
    Reporting group description
    		 Treatment B – Control arm Placebo tablet once a day for 3 days, then twice a day until surgery (between 1 and 5 weeks)

    Primary: Post treatment Ki-67 expression

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    End point title
    		 Post treatment Ki-67 expression
    End point description
    End point type
    Primary
    End point timeframe
    Post treatment timepoint adjusted for Baseline expression
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    45
    43
    Units: %
        arithmetic mean (confidence interval 95%)
    32.8 (28.0 to 37.6)
    33.9 (28.2 to 39.7)
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.57
         upper limit
    		 6.42
    Notes
    [1] - Linear ANCOVA adjusted for baseline expression

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Metformin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Metformin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 47 (78.72%)
    25 / 46 (54.35%)
    Cardiac disorders
    PALPITATIONS
    Additional description: PALPITATIONS
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    2
    Nervous system disorders
    HEADACHE
    Additional description: HEADACHE
         subjects affected / exposed
    5 / 47 (10.64%)
    0 / 46 (0.00%)
         occurrences all number
    5
    0
    General disorders and administration site conditions
    DIZZINESS
    Additional description: DIZZINESS
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 46 (4.35%)
         occurrences all number
    3
    2
    FATIGUE
    Additional description: FATIGUE
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 46 (2.17%)
         occurrences all number
    5
    1
    NON-SPECIFICALLY UNWELL
    Additional description: NON-SPECIFICALLY UNWELL
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    Eye disorders
    BLURRY EYES
    Additional description: BLURRY EYES
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    DRY EYES
    Additional description: DRY EYES
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    ABDOMINAL PAIN
    Additional description: ABDOMINAL PAIN
         subjects affected / exposed
    11 / 47 (23.40%)
    6 / 46 (13.04%)
         occurrences all number
    11
    6
    ANOREXIA
    Additional description: ANOREXIA
         subjects affected / exposed
    9 / 47 (19.15%)
    0 / 46 (0.00%)
         occurrences all number
    9
    0
    BLOATING/FLATULENCE
    Additional description: BLOATING/FLATULENCE
         subjects affected / exposed
    6 / 47 (12.77%)
    2 / 46 (4.35%)
         occurrences all number
    6
    2
    CONSTIPATION
    Additional description: CONSTIPATION
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 46 (2.17%)
         occurrences all number
    4
    1
    DIARRHOEA
    Additional description: DIARRHOEA
         subjects affected / exposed
    23 / 47 (48.94%)
    6 / 46 (13.04%)
         occurrences all number
    32
    7
    DRY MOUTH
    Additional description: DRY MOUTH
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    GASTROESOPHAGEAL REFLUX
    Additional description: GASTROESOPHAGEAL REFLUX
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    NAUSEA AND VOMITTING
    Additional description: NAUSEA AND VOMITTING
         subjects affected / exposed
    17 / 47 (36.17%)
    6 / 46 (13.04%)
         occurrences all number
    29
    7
    PARAGEUSIA
    Additional description: PARAGEUSIA
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 46 (4.35%)
         occurrences all number
    3
    2
    Reproductive system and breast disorders
    BLEEDING
    Additional description: BLEEDING
         subjects affected / exposed
    2 / 47 (4.26%)
    3 / 46 (6.52%)
         occurrences all number
    2
    3
    HOT FLUSHES
    Additional description: HOT FLUSHES
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    COUGH
    Additional description: COUGH
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    SHORTNESS OF BREATH
    Additional description: SHORTNESS OF BREATH
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    EXACERBATION OF PSORIASIS
    Additional description: EXACERBATION OF PSORIASIS
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1
    RASH/ITCHING
    Additional description: RASH/ITCHING
         subjects affected / exposed
    6 / 47 (12.77%)
    2 / 46 (4.35%)
         occurrences all number
    7
    3
    Renal and urinary disorders
    IMPAIRED RENAL FUNCTION
    Additional description: IMPAIRED RENAL FUNCTION
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    HUNGRY FOR SUGAR
    Additional description: HUNGRY FOR SUGAR
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
    Additional description: BACK PAIN
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    LEG CRAMPS
    Additional description: LEG CRAMPS
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    MUSCLE ACHES
    Additional description: MUSCLE ACHES
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    TOOTH ABCESS
    Additional description: TOOTH ABCESS
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2014
    Change of trial name to assist with public engagement. Addition of omental biopsy during hysterectomy to enable exploratory work investigating the effect of metformin on adipose tissue proliferation, metabolism and communication with endometrial cancer cells through the generation of a novel adipocyte and endometrial cancer cell co-culture system.

    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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