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    Clinical Trial Results:
    Proof of mechanism pre-surgical window trial of metformin in non-diabetic women with endometrial carcinoma: a feasibility study

    Summary
    EudraCT number
    2011-001382-40
    Trial protocol
    GB  
    Global end of trial date
    30 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Apr 2020
    First version publication date
    25 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    R01602
    Additional study identifiers
    ISRCTN number
    ISRCTN81570194
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    REF reference: 11/NW/0442
    Sponsors
    Sponsor organisation name
    Manchester University NHS Foundation Trust
    Sponsor organisation address
    29 Grafton Street, Manchester, United Kingdom, M13 9WU
    Public contact
    Dr Lynne Webster, Manchester University NHS Foundation Trust, +44 01612764125, research.sponsor@mft.nhs.uk
    Scientific contact
    Dr Lynne Webster, Manchester University NHS Foundation Trust, +44 01612764125, research.sponsor@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
    30 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether metformin exerts any effect when given prior to hysterectomy surgery in non diabetic women with endometrial cancer.
    Protection of trial subjects
    Interviews and biological samples will be collected at a time when the patient would already be in the clinic being reviewed by clinical staff. This can be rescheduled if not convenient. The endometrial biopsies were only taken by senior experienced clinicians with expertise in this potentially embarrassing and uncomfortable procedure. There were female chaperones present at all intimate examinations. The examination would have been abandoned if the patient told us they were finding it extremely painful. Although the safety profile of Metformin is well known and well tolerated, its use in women with endometrial cancer was not known. We therefore closely monitored the patients whilst they are taking the drug. Any safety concerns were recorded. Any patients unable to tolerate metformin or who experience serious adverse events whilst taking it will be advised to discontinue treatment.
    Background therapy
    There is no background therapy for the trial.
    Evidence for comparator
    Metformin is the only drug in the trial, there is no comparator drug.
    Actual start date of recruitment
    09 Nov 2011
    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: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    20
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    36 patients were recruited to the metformin arm - 35 received the treatment and 1 was a screen failure. 15 patients were recruited to the untreated control arm of the trial.

    Pre-assignment
    Screening details
    101 patients were screened for eligibility between October 2012 and February 2014. 65 were not eligible or declined the metformin treatment.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    This was a single-arm trial with no control.

    Arms
    Arm title
    Metformin-treated
    Arm description
    Women were given Metformin 850mg BD for 2-4 weeks until surgery.
    Arm type
    Experimental

    Investigational medicinal product name
    Metformin hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Maximum allowed dose: 1700mg per day. Maximum duration of treatment: 4 weeks. Boxes of coated tablets of metformin hydrochloride 850mg will be supplied to study participants on the second visit after obtaining fasted blood samples and the endometrial biopsy. To enable the return of the IMP, a prepaid addressed envelope will be provided at the second visit. Each patient will take one 850mg tablet twice a day from recruitment into the study until surgery (at least two weeks and up to four weeks total time period). The number of tablets dispensed will be fifty-six in all cases. Boxes will be dispensed by the Clinical Trials Pharmacy at CMFT and labelled as Investigational Medicinal Product (IMP). Boxes will be prescribed for an individual, named patient who has provided written informed consent to participate in the trial. Boxes of metformin will be stored in the pharmacy according to the manufacturer’s instructions until suitable patients are recruited.

    Number of subjects in period 1
    Metformin-treated
    Started
    36
    Completed
    35
    Not completed
    1
         Screen failure
    1
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    This was a single arm trial with no control.

    Arms
    Arm title
    Metformin
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Metformin hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Maximum allowed dose: 1700mg per day. Maximum duration of treatment: 4 weeks. Boxes of coated tablets of metformin hydrochloride 850mg will be supplied to study participants on the second visit after obtaining fasted blood samples and the endometrial biopsy. To enable the return of the IMP, a prepaid addressed envelope will be provided at the second visit. Each patient will take one 850mg tablet twice a day from recruitment into the study until surgery (at least two weeks and up to four weeks total time period). The number of tablets dispensed will be fifty-six in all cases. Boxes will be dispensed by the Clinical Trials Pharmacy at CMFT and labelled as Investigational Medicinal Product (IMP). Boxes will be prescribed for an individual, named patient who has provided written informed consent to participate in the trial. Boxes of metformin will be stored in the pharmacy according to the manufacturer’s instructions until suitable patients are recruited.

    Number of subjects in period 2
    Metformin
    Started
    35
    Completed
    28
    Not completed
    7
         Adverse event, non-fatal
    4
         Protocol deviation
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Metformin-treated
    Reporting group description
    Women were given Metformin 850mg BD for 2-4 weeks until surgery.

    Reporting group values
    Metformin-treated Total
    Number of subjects
    36 36
    Age categorical
    Units: Subjects
        Less than 50
    2 2
        51-60
    14 14
        61-70
    14 14
        71-80
    5 5
        Greater than 80
    1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    62.0 ( 9.8 ) -
    Gender categorical
    Units: Subjects
        Female
    36 36
        Male
    0 0
    BMI
    Units: Subjects
        Less than 25
    6 6
        25-29.9
    8 8
        30-39.9
    10 10
        Greater than 40
    11 11
        Missing
    1 1
    Smoking habits
    Units: Subjects
        Nonsmoker
    18 18
        Ex-smoker
    12 12
        Current smoker
    5 5
        Missing
    1 1
    Daily alcoholic units
    Units: Subjects
        None
    14 14
        Less than or equal to 2
    11 11
        Greater than 2
    2 2
        Missing
    9 9
    Insulin resistance
    Units: Subjects
        HOMA-IR greater than 2.8
    18 18
        HOMA-IR less than or equal to 2.8
    17 17
        Missing
    1 1
    Tumour grade at hysterectomy
    Units: Subjects
        AEH
    0 0
        G1
    17 17
        G2
    14 14
        G3
    4 4
        Missing
    1 1
    FIGO stage at hysterectomy
    Units: Subjects
        1A
    20 20
        1B
    3 3
        Two
    2 2
        Three
    3 3
        Missing
    8 8
    Lymphovascular space invasion present
    Units: Subjects
        Yes
    12 12
        No
    20 20
        Missing
    4 4
    Myometrial invasion
    Units: Subjects
        Less than 50%
    23 23
        Greater than or equal to 50%
    8 8
        Missing
    5 5
    Follow-up and adjuvant therapy
    Units: Subjects
        Clinical follow-up
    20 20
        Chemotherapy alone
    4 4
        Chemotherapy, EBRT & VB
    5 5
        VB: Vaginal brachytherapy
    2 2
        EBRT: External beam radiotherapy
    1 1
        Missing
    3 3
        VB & EBRT
    1 1
    ER expression
    Units: Subjects
        Positive
    28 28
        Negative
    0 0
        Missing
    8 8
    PR expression
    Units: Subjects
        Positive
    28 28
        Negative
    0 0
        Missing
    8 8
    PTEN expression
    Units: Subjects
        Wild type
    19 19
        Mutant
    9 9
        Missing
    8 8
    P53 expression
    Units: Subjects
        Wild type
    27 27
        Mutant
    1 1
        Missing
    8 8
    BMI
    Units: kg m-2
        arithmetic mean (standard deviation)
    35.3 ( 11.2 ) -
    Waist/hip girth ratio
    Units: ratio
        arithmetic mean (standard deviation)
    0.88 ( 0.06 ) -
    HOMA-IR index
    Units: Index
        arithmetic mean (standard deviation)
    3.97 ( 2.62 ) -
    Ki-67 proliferation index
    Units: Percentage
        arithmetic mean (standard deviation)
    50.9 ( 17.1 ) -
    Glucose
    Units: mmol/l
        arithmetic mean (standard deviation)
    6.0 ( 1.5 ) -
    Insulin
    Units: mU/l
        arithmetic mean (standard deviation)
    16.0 ( 9.4 ) -
    C-peptide
    Units: pmol/l
        arithmetic mean (standard deviation)
    1076.1 ( 482.3 ) -
    Adiponectin
    Units: mg/l
        arithmetic mean (standard deviation)
    3.3 ( 1.5 ) -
    Leptin
    Units: mg/ml
        arithmetic mean (standard deviation)
    54.1 ( 42.6 ) -
    Ln (hsCRP)
    Units: mg/l
        arithmetic mean (standard deviation)
    1.3 ( 1.3 ) -

    End points

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    End points reporting groups
    Reporting group title
    Metformin-treated
    Reporting group description
    Women were given Metformin 850mg BD for 2-4 weeks until surgery.
    Reporting group title
    Metformin
    Reporting group description
    -

    Primary: Ki-67 proliferation

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    End point title
    Ki-67 proliferation [1]
    End point description
    End point type
    Primary
    End point timeframe
    Post-treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Patients in this study were compared to a non-randomised control group of individuals recruited onto an independent study. There were no separate statistical analyses for the Metformin data alone. In our paper, the primary endpoint, change in tumour Ki-67 proliferation index after adjustment for baseline Ki-67, age, BMI, insulin resistance and change in the control group was found to be -17.2 (95% CI -27.4, -4.0%), compared to 13.5% (SD 15.5) for the Metformin group alone.
    End point values
    Metformin
    Number of subjects analysed
    28
    Units: Percentage
        arithmetic mean (standard deviation)
    37.4 ( 29.0 )
    No statistical analyses for this end point

    Secondary: Glucose

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    End point title
    Glucose
    End point description
    End point type
    Secondary
    End point timeframe
    Post-treatment
    End point values
    Metformin
    Number of subjects analysed
    28
    Units: mmol/l
        arithmetic mean (standard deviation)
    5.5 ( 1.3 )
    No statistical analyses for this end point

    Secondary: Insulin

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    End point title
    Insulin
    End point description
    End point type
    Secondary
    End point timeframe
    Post-treatment
    End point values
    Metformin
    Number of subjects analysed
    28
    Units: mU/l
        arithmetic mean (standard deviation)
    9.9 ( 7.1 )
    No statistical analyses for this end point

    Secondary: HOMA-IR

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    End point title
    HOMA-IR
    End point description
    End point type
    Secondary
    End point timeframe
    Post-treatment
    End point values
    Metformin
    Number of subjects analysed
    28
    Units: Scale
        arithmetic mean (standard deviation)
    2.5 ( 2.0 )
    No statistical analyses for this end point

    Secondary: C-peptide

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    End point title
    C-peptide
    End point description
    End point type
    Secondary
    End point timeframe
    Post-treatment
    End point values
    Metformin
    Number of subjects analysed
    28
    Units: pmol/l
        arithmetic mean (standard deviation)
    985.4 ( 525.3 )
    No statistical analyses for this end point

    Secondary: Adiponectin

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    End point title
    Adiponectin
    End point description
    End point type
    Secondary
    End point timeframe
    Post-treatment
    End point values
    Metformin
    Number of subjects analysed
    28
    Units: mg/l
        arithmetic mean (standard deviation)
    2.8 ( 1.1 )
    No statistical analyses for this end point

    Secondary: Leptin

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    End point title
    Leptin
    End point description
    End point type
    Secondary
    End point timeframe
    Post-treatment
    End point values
    Metformin
    Number of subjects analysed
    28
    Units: ng/ml
        arithmetic mean (standard deviation)
    57.9 ( 46.7 )
    No statistical analyses for this end point

    Secondary: Ln(hsCRP)

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    End point title
    Ln(hsCRP)
    End point description
    End point type
    Secondary
    End point timeframe
    Post-treatment
    End point values
    Metformin
    Number of subjects analysed
    28
    Units: mg/l
        arithmetic mean (standard deviation)
    0.8 ( 1.4 )
    No statistical analyses for this end point

    Secondary: Body mass index

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    End point title
    Body mass index
    End point description
    End point type
    Secondary
    End point timeframe
    Post-treatment
    End point values
    Metformin
    Number of subjects analysed
    28
    Units: kg/m2
        arithmetic mean (standard deviation)
    35.1 ( 10.9 )
    No statistical analyses for this end point

    Secondary: Waist/hip girth ratio

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    End point title
    Waist/hip girth ratio
    End point description
    End point type
    Secondary
    End point timeframe
    Post-treatment
    End point values
    Metformin
    Number of subjects analysed
    28
    Units: Ratio
        arithmetic mean (standard deviation)
    0.9 ( 0.1 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Patients will be contacted by telephone after one to two weeks of metformin treatment to ensure tolerability and to check for adverse events.
    Adverse event reporting additional description
    Any SAE will be reported by the Principal Investigator (including a completed SAE form) within 24 hours of first knowledge to the Sponsor. The Principal Investigator will ensure that the patient is appropriately treated. They will also determine whether the SAE is a SUSAR (Suspected Unexpected Serious Adverse Reaction).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Metformin
    Reporting group description
    -

    Serious adverse events
    Metformin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 35 (2.86%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Atrial fibrillation
    Additional description: Patient 020 (14th August 2013): Atrial fibrillation (hospitalisation); unlikely to be related to study IMP.
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Metformin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 35 (77.14%)
    Investigations
    Abnormal baseline bloods
    Additional description: 10 participants experienced this AE.
         subjects affected / exposed
    10 / 35 (28.57%)
         occurrences all number
    10
    Nervous system disorders
    Headache
    Additional description: 3 participants experienced this AE.
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    General disorders and administration site conditions
    Fatigue
    Additional description: 2 participants experienced this AE.
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Gastrointestinal disorders
    Diarrhoea
    Additional description: 24 participants experienced this AE.
         subjects affected / exposed
    24 / 35 (68.57%)
         occurrences all number
    24
    Loss of appetite
    Additional description: 4 participants experienced this AE.
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    4
    Nausea/vomiting
    Additional description: 27 participants experienced this AE.
         subjects affected / exposed
    27 / 35 (77.14%)
         occurrences all number
    27
    Abdominal pain
    Additional description: 12 participants experienced this AE.
         subjects affected / exposed
    12 / 35 (34.29%)
         occurrences all number
    12
    Bloating
    Additional description: 2 participants experienced this AE.
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Others
    Additional description: 11 participants experienced other AEs.
         subjects affected / exposed
    11 / 35 (31.43%)
         occurrences all number
    11
    Skin and subcutaneous tissue disorders
    Skin changes
    Additional description: 3 participants experienced this AE.
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2011
    Substantial amendment 1: (1) To restrict entry to the study to patients with type 1 endometrial cancer. (2) To perform some laboratory analysis at the Wolfson Molecular Imaging Centre. (3) To ask participants to return to St Mary's to have they final blood test and endometrial biopsy taken ahead of surgery in the event that surgery is delayed beyond four weeks. (4) To amend the PIS to reflect the above changes. This amendment also required a change to the protocol (V3.0). R&D approval for the amendment was issued 26/01/2012.
    29 Aug 2012
    Substantial amendment 2: (1) To state that a Part 1 of the Participant Information Sheet will be sent to potential participants with their letter inviting them to attend their pre-operative gynaecological clinic. (2) To clarify that two visits will be required in order to obtain blood samples prior to starting treatment with metformin. (3) To update the Participant Information Sheet to reflect the above change (point 2). (4) To amend the Protocol to state that metformin will be dispensed at the pre-admission clinic and participants instructed to begin treatment if the renal function is within permissible range. (5) To make a number of minor changes to the Protocol. This amendment updated the protocol to V4.0. R&D approval was issued 21/09/2012.
    01 Feb 2013
    Substantial amendment 4: Amendment to include patients with atypical hyperplasia and patients with shorter window periods to increase participant numbers. This amendment updated the protocol to V5.0. R&D approval was issued 14/03/2013.

    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.
    N/A

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26794276
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