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    Clinical Trial Results:
    Metformin treatment vs a diabetes model of antenatal care in women with mild fasting hyperglycaemia diagnosed in pregnancy: a pilot study

    Summary
    EudraCT number
    2013-004065-13
    Trial protocol
    GB  
    Global end of trial date
    04 Jan 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    02 May 2020
    First version publication date
    02 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Metform02
    Additional study identifiers
    ISRCTN number
    -
    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
    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
    04 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study aims to assess the acceptability and feasibility of using a simple treatment with tablets (metformin) for women with mild gestational diabetes. Metformin is safe in pregnancy and has the advantage that frequent blood glucose monitoring is not necessary. We hope this treatment will be effective in reducing the number of babies which gain excessive weight in pregnancy, without the need for frequent hospital visits and high intervention rates which are associated with the intensive antenatal care routinely offered to women with gestational diabetes.
    Protection of trial subjects
    Metformin is associated with a number of gastrointestinal side effects and women unable to tolerate the drug will be advised to discontinue (<5% from previous studies). Although metformin treatment aims to reduce blood glucose levels before and after eating, serious hypoglycaemia is very uncommon and metformin is prescribed in several settings without regular blood glucose monitoring. Women randomised to the diabetic antenatal care arm of the study will be asked to perform regular blood glucose monitoring (BGM). This is an onerous task for women in pregnancy but is standard practice within diabetic antenatal clinics. Women who have HBGM outside the target range will be prescribed metformin and those who do not meet target control with metformin will be prescribed adjuvant insulin. This prescribing regime will be in line with current prescribing practices within our hospital. Women in this arm of the study will also be offered monthly ultrasound scans to assess fetal growth. It is usual practice to offer induction of labour to women with a macrosomic fetus (>95th centile)and therefore some women in this group will be offered additional obstetric interventions. Metformin can sometimes cause some stomach upset (sickness and diarrhoea) so the dose will be increased slowly to minimise this side effect. Metformin can also cause taste disturbance and affect appetite. There is a very rare (<1/10,000), but serious side effect of metformin called ‘lactic acidosis’. This occurs in individuals with kidney or liver problems. We will perform a blood test at the beginning of the study to ensure that you do not have any liver or kidney problems before you start the metformin tablets to ensure that the treatment is safe for you. Other very rare side effects include skin rashes.
    Background therapy
    Standard diabetes antenatal care (NICE diabetes guidelines) with HBGM and scan surveillance.
    Evidence for comparator
    The pregnancy outcomes for all women, delivered at St Mary’s Hospital Manchester in 2010, who had an oral glucose tolerance test (OGTT) which would fit the proposed IADPSG diagnostic criteria, have recently been reviewed. 4% of all women who had an OGTT had isolated mild fasting hyperglycaemia (fasting 5.1-5.4 mmol/L; 2 hour <8.5mmol/L). All of these women were managed in normal antenatal clinics with no treatment. The frequency of large for gestational age babies (LGA) in this group (defined as >95th centile using centiles adjusted for maternal characteristics, fetal gender and gestation) was 16.4% (95% CI 9.0-27.8%), more than three times the expected frequency. In addition, we have analysed the Manchester data collected as part the HAPO study (n=2388). In this cohort, 201 women (8%) had a fasting blood glucose level between 5.1 and 5.4 mmol/L (normal 2 hour; <8.5mmol/L). The frequency of LGA (>95th centile) in this group was 9.0% compared to 3.9% (p=0.002) in the normoglycaemic group (n=1886) (OR 2.2 (95% CI 1.4-3.3). This data also suggests that the frequency of macrosomic infants delivered to women with mild degrees of fasting hyperglycaemia in the third trimester is unacceptably high. It is therefore timely to determine whether a simple intervention in this group could reduce the number of macrosomic infants delivered. This pilot study will assess the acceptability of metformin, prescribed in conjunction with routine antenatal care, compared to a standard diabetic model of antenatal care. In the study arm, metformin will be titrated up to the maximum tolerated dose in the absence of home blood glucose monitoring (HBGM). Women in the standard diabetic clinic arm will have their treatment titrated according to HBGM with the addition of insulin where blood glucose levels are out of target, this will allow us to make an assessment of the effectiveness of metformin in this group of women with mild fasting hyperglycaemia.
    Actual start date of recruitment
    02 Dec 2013
    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: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Over the course of this study we aim to recruit 60 women.

    Pre-assignment
    Screening details
    Women with risk factors for GDM (NICE 2008) will be offered an oral glucose tolerance test (OGTT) at 26 weeks gestation as part of their routine antenatal care. Women with mild GDM (Fasting 5.1mmol/l­ 5.4 mmol/L; 2­hour <8.5 mmol/l) will be recruited into the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Metformin
    Arm description
    Women randomised to the study arm (Metformin only treatment arm) will be prescribed metformin tablets up to 2000mg from randomisation (26-28 weeks gestation) and will stop once they have delivered their baby. Women will be asked to start with 500mg metformin (1 tablet, Once Daily) taken with food, increasing on Day 4 by an increment of 500mg per day (in other words to 1 tablet, twice daily). Day 7: a further increment of 500mg per day (in other words to 1 tablet, three times daily). On Day 14, women will increase the evening dose of metformin by a further 500mg. If side effects (largely anticipated to be gastro-intestinal) are experienced, the woman should drop to the previous dose or 500mg metformin (whichever is the greater) and wait for 3 days before increasing the dosage again. The maximum recommended dose is 2000mg daily, taken as three divided doses. The usual starting dose is one tablet 2 or 3 times daily given during or after meals.
    Arm type
    Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Women randomised to the study arm (Metformin only treatment arm) will be prescribed metformin tablets up to 2000mg from randomisation (26-28 weeks gestation) and will stop once they have delivered their baby. Women will be asked to start with 500mg metformin (1 tablet, Once Daily) taken with food, increasing on Day 4 by an increment of 500mg per day (in other words to 1 tablet, twice daily). Day 7: a further increment of 500mg per day (in other words to 1 tablet, three times daily). On Day 14, women will increase the evening dose of metformin by a further 500mg. If side effects (largely anticipated to be gastro-intestinal) are experienced, the woman should drop to the previous dose or 500mg metformin (whichever is the greater) and wait for 3 days before increasing the dosage again. The maximum recommended dose is 2000mg daily, taken as three divided doses. The usual starting dose is one tablet 2 or 3 times daily given during or after meals.

    Arm title
    Standard care
    Arm description
    In addition to dietary advice and lifestyle advice, women in the standard care arm will be issued with a HBGM meter and asked to record capillary blood glucose before and 1 hour after meals (x 7/day) with target glucose ranges of fasting <5.5 and 1 hour post prandial <7.8mmol/L. Women will be provided with a contact telephone number and asked to contact the research midwife if the blood sugars are outside the target range on 3 or more occasions within one week. The handheld maternity records will be updated to inform health care professionals that the woman is participating in the trial and has been randomised to the standard care arm. A baseline ultrasound to assess fetal growth will be performed at study visit 1. Women will be reviewed in the research clinic 2 weeks after their initial appointment.
    Arm type
    model of care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Metformin Standard care
    Started
    20
    20
    Completed
    17
    19
    Not completed
    3
    1
         Transferred care
    1
    -
         Physician decision
    2
    -
         Discontinued intervention
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Metformin
    Reporting group description
    Women randomised to the study arm (Metformin only treatment arm) will be prescribed metformin tablets up to 2000mg from randomisation (26-28 weeks gestation) and will stop once they have delivered their baby. Women will be asked to start with 500mg metformin (1 tablet, Once Daily) taken with food, increasing on Day 4 by an increment of 500mg per day (in other words to 1 tablet, twice daily). Day 7: a further increment of 500mg per day (in other words to 1 tablet, three times daily). On Day 14, women will increase the evening dose of metformin by a further 500mg. If side effects (largely anticipated to be gastro-intestinal) are experienced, the woman should drop to the previous dose or 500mg metformin (whichever is the greater) and wait for 3 days before increasing the dosage again. The maximum recommended dose is 2000mg daily, taken as three divided doses. The usual starting dose is one tablet 2 or 3 times daily given during or after meals.

    Reporting group title
    Standard care
    Reporting group description
    In addition to dietary advice and lifestyle advice, women in the standard care arm will be issued with a HBGM meter and asked to record capillary blood glucose before and 1 hour after meals (x 7/day) with target glucose ranges of fasting <5.5 and 1 hour post prandial <7.8mmol/L. Women will be provided with a contact telephone number and asked to contact the research midwife if the blood sugars are outside the target range on 3 or more occasions within one week. The handheld maternity records will be updated to inform health care professionals that the woman is participating in the trial and has been randomised to the standard care arm. A baseline ultrasound to assess fetal growth will be performed at study visit 1. Women will be reviewed in the research clinic 2 weeks after their initial appointment.

    Reporting group values
    Metformin Standard care Total
    Number of subjects
    20 20 40
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    20 20 40
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    31 (26 to 34) 33 (28 to 35) -
    Gender categorical
    Units: Subjects
        Female
    20 20 40
        Male
    0 0 0
    Smokers
    Units: Subjects
        Yes
    1 0 1
        No
    19 20 39
    Ethnicity
    Units: Subjects
        White
    7 4 11
        Black
    4 5 9
        Asian
    6 7 13
        Other
    3 4 7
    BMI
    Units: ratio
        median (inter-quartile range (Q1-Q3))
    31 (27.5 to 35.0) 29 (25.5 to 34.0) -
    Parity
    Units: Count
        median (inter-quartile range (Q1-Q3))
    1 (0 to 2) 1 (0 to 2) -
    Fasting gllucose at OGTT
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    5.2 (5.10 to 5.30) 5.2 (5.15 to 5.35) -
    2H glucose at OGTT
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    6.50 (5.55 to 7.05) 5.95 (4.70 to 6.90) -
    HbA1c at baseline
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    33.5 (30.0 to 35.0) 32.0 (29.0 to 37.0) -

    End points

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    End points reporting groups
    Reporting group title
    Metformin
    Reporting group description
    Women randomised to the study arm (Metformin only treatment arm) will be prescribed metformin tablets up to 2000mg from randomisation (26-28 weeks gestation) and will stop once they have delivered their baby. Women will be asked to start with 500mg metformin (1 tablet, Once Daily) taken with food, increasing on Day 4 by an increment of 500mg per day (in other words to 1 tablet, twice daily). Day 7: a further increment of 500mg per day (in other words to 1 tablet, three times daily). On Day 14, women will increase the evening dose of metformin by a further 500mg. If side effects (largely anticipated to be gastro-intestinal) are experienced, the woman should drop to the previous dose or 500mg metformin (whichever is the greater) and wait for 3 days before increasing the dosage again. The maximum recommended dose is 2000mg daily, taken as three divided doses. The usual starting dose is one tablet 2 or 3 times daily given during or after meals.

    Reporting group title
    Standard care
    Reporting group description
    In addition to dietary advice and lifestyle advice, women in the standard care arm will be issued with a HBGM meter and asked to record capillary blood glucose before and 1 hour after meals (x 7/day) with target glucose ranges of fasting <5.5 and 1 hour post prandial <7.8mmol/L. Women will be provided with a contact telephone number and asked to contact the research midwife if the blood sugars are outside the target range on 3 or more occasions within one week. The handheld maternity records will be updated to inform health care professionals that the woman is participating in the trial and has been randomised to the standard care arm. A baseline ultrasound to assess fetal growth will be performed at study visit 1. Women will be reviewed in the research clinic 2 weeks after their initial appointment.

    Primary: Study compliance

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    End point title
    Study compliance [1]
    End point description
    End point type
    Primary
    End point timeframe
    Over study duration
    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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    End point values
    Metformin Standard care
    Number of subjects analysed
    20
    20
    Units: Subjects
    17
    19
    No statistical analyses for this end point

    Primary: Intervention compliance with 2g

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    End point title
    Intervention compliance with 2g [2] [3]
    End point description
    End point type
    Primary
    End point timeframe
    Overall
    Notes
    [2] - 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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a treatment specific endpoint designed to inform the future study around treatment adherence. Therefore it is not relevant to the control group and there is no equivalent measure.
    End point values
    Metformin
    Number of subjects analysed
    13
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    68 (48 to 85)
    No statistical analyses for this end point

    Primary: Maximum metformin dose

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    End point title
    Maximum metformin dose [4] [5]
    End point description
    End point type
    Primary
    End point timeframe
    Whole study
    Notes
    [4] - 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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This is a treatment specific endpoint designed to inform the future study around treatment adherence. Therefore it is not relevant to the control group and there is no equivalent measure.
    End point values
    Metformin
    Number of subjects analysed
    15
    Units: mg
        median (inter-quartile range (Q1-Q3))
    2000 (1000 to 2000)
    No statistical analyses for this end point

    Primary: Happy to participate

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    End point title
    Happy to participate [6]
    End point description
    End point type
    Primary
    End point timeframe
    Completion
    Notes
    [6] - 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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    End point values
    Metformin Standard care
    Number of subjects analysed
    19
    17
    Units: Subjects
        Yes
    18
    17
        No
    1
    0
    No statistical analyses for this end point

    Primary: When you started the study, how did you feel about your allocation?

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    End point title
    When you started the study, how did you feel about your allocation? [7]
    End point description
    End point type
    Primary
    End point timeframe
    Duration
    Notes
    [7] - 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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    End point values
    Metformin Standard care
    Number of subjects analysed
    18
    17
    Units: Subjects
        Not satisfied
    0
    0
        Satisfied
    15
    14
        Not sure
    3
    2
        Missing
    0
    1
    No statistical analyses for this end point

    Primary: Now you have completed the study, how do you feel about your allocation?

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    End point title
    Now you have completed the study, how do you feel about your allocation? [8]
    End point description
    End point type
    Primary
    End point timeframe
    End of study
    Notes
    [8] - 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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    End point values
    Metformin Standard care
    Number of subjects analysed
    18
    17
    Units: Subjects
        Not satisfied
    0
    0
        Satisfied
    18
    17
        Not sure
    0
    0
        Missing
    0
    0
    No statistical analyses for this end point

    Primary: How do you feel about your antenatal care since you enrolled in the study?

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    End point title
    How do you feel about your antenatal care since you enrolled in the study? [9]
    End point description
    End point type
    Primary
    End point timeframe
    Duration
    Notes
    [9] - 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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    End point values
    Metformin Standard care
    Number of subjects analysed
    18
    17
    Units: subjects
        Not satisfied
    0
    0
        Satisfied
    18
    17
        Not sure
    0
    0
        Missing
    0
    0
    No statistical analyses for this end point

    Primary: If the study included a 'no treatment' allocation, would you have still been happy to take part in the study?

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    End point title
    If the study included a 'no treatment' allocation, would you have still been happy to take part in the study? [10]
    End point description
    End point type
    Primary
    End point timeframe
    Duration
    Notes
    [10] - 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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    End point values
    Metformin Standard care
    Number of subjects analysed
    18
    17
    Units: Subjects
        Yes
    14
    16
        No
    4
    1
        Missing
    0
    0
    No statistical analyses for this end point

    Primary: How often did you forget to take your medication?

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    End point title
    How often did you forget to take your medication? [11]
    End point description
    End point type
    Primary
    End point timeframe
    Duration
    Notes
    [11] - 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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    End point values
    Metformin Standard care
    Number of subjects analysed
    18
    17
    Units: Subjects
        No medication
    0
    4
        Never or rarely
    12
    8
        1-3 times/wk
    5
    5
        4-6 times/wk
    0
    0
        >6 times/wk
    1
    0
        Missing
    0
    0
    No statistical analyses for this end point

    Primary: Which part of your diabetes treatment was easiest?

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    End point title
    Which part of your diabetes treatment was easiest? [12]
    End point description
    End point type
    Primary
    End point timeframe
    Duration
    Notes
    [12] - 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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    End point values
    Metformin Standard care
    Number of subjects analysed
    18
    17
    Units: Subjects
        Doing finger-prick tests
    0
    7
        Being careful with diet
    1
    2
        Taking medication
    16
    7
        Missing
    1
    1
    No statistical analyses for this end point

    Primary: Which part of your diabetes treatment was hardest?

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    End point title
    Which part of your diabetes treatment was hardest? [13]
    End point description
    End point type
    Primary
    End point timeframe
    Duration
    Notes
    [13] - 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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    End point values
    Metformin Standard care
    Number of subjects analysed
    18
    17
    Units: Subjects
        Doing finger-prick tests
    0
    7
        Being careful with diet
    12
    9
        Taking medication
    4
    0
        Missing
    2
    1
    No statistical analyses for this end point

    Primary: In future pregnancy, if you developed diabetes again, would you choose?

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    End point title
    In future pregnancy, if you developed diabetes again, would you choose? [14]
    End point description
    End point type
    Primary
    End point timeframe
    Duration
    Notes
    [14] - 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: This is a feasibility study with feasibility outcomes looking at recruitment and acceptability and for this type of endpoint no statistical analysis is required. The first outcome is recruitment. 147 women out of 173 women with OGTT results meeting the study criteria met the inclusion criteria for the trial. Of these women, 40 women (27%) agreed to take part in the study.
    End point values
    Metformin Standard care
    Number of subjects analysed
    18
    17
    Units: Subjects
        Monitoring in a diabetic antenatal clinic
    8
    15
        Metformin, no home blood glucose / hospital visits
    9
    0
        No treatment at all
    1
    1
        Missing
    0
    1
    No statistical analyses for this end point

    Secondary: HbA1C at 36-38 weeks

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    End point title
    HbA1C at 36-38 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    36-38 weeks
    End point values
    Metformin Standard care
    Number of subjects analysed
    20
    20
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    35.5 (31.0 to 40.0)
    37.0 (35.0 to 41.0)
    No statistical analyses for this end point

    Secondary: Number of "none diabetes" scans

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    End point title
    Number of "none diabetes" scans
    End point description
    End point type
    Secondary
    End point timeframe
    Secondary
    End point values
    Metformin Standard care
    Number of subjects analysed
    20
    20
    Units: Range
        median (inter-quartile range (Q1-Q3))
    3 (2 to 5)
    5 (0 to 9)
    No statistical analyses for this end point

    Secondary: Number of clinic attendances post randomisation

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    End point title
    Number of clinic attendances post randomisation
    End point description
    End point type
    Secondary
    End point timeframe
    Duration
    End point values
    Metformin Standard care
    Number of subjects analysed
    20
    20
    Units: Range
        median (inter-quartile range (Q1-Q3))
    2.5 (2 to 5)
    7 (4 to 9)
    No statistical analyses for this end point

    Secondary: Number of phone calls

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    End point title
    Number of phone calls
    End point description
    End point type
    Secondary
    End point timeframe
    Duration
    End point values
    Metformin Standard care
    Number of subjects analysed
    20
    20
    Units: Number
        median (inter-quartile range (Q1-Q3))
    2 (1 to 4)
    2 (0 to 2)
    No statistical analyses for this end point

    Secondary: Number of admissions

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    End point title
    Number of admissions
    End point description
    End point type
    Secondary
    End point timeframe
    Duration
    End point values
    Metformin Standard care
    Number of subjects analysed
    20
    20
    Units: Admissions
    1
    0
    No statistical analyses for this end point

    Secondary: Spontaneous labour onset

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    End point title
    Spontaneous labour onset
    End point description
    End point type
    Secondary
    End point timeframe
    Labour
    End point values
    Metformin Standard care
    Number of subjects analysed
    19
    20
    Units: Subjects
    5
    6
    No statistical analyses for this end point

    Secondary: Delivery - vaginal

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    End point title
    Delivery - vaginal
    End point description
    End point type
    Secondary
    End point timeframe
    Labour
    End point values
    Metformin Standard care
    Number of subjects analysed
    19
    20
    Units: Subjects
    11
    15
    No statistical analyses for this end point

    Secondary: Gestation at delivery

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    End point title
    Gestation at delivery
    End point description
    End point type
    Secondary
    End point timeframe
    Delivery
    End point values
    Metformin Standard care
    Number of subjects analysed
    19
    20
    Units: Days
        median (inter-quartile range (Q1-Q3))
    278 (270 to 282)
    273 (270 to 276)
    No statistical analyses for this end point

    Secondary: LGA (greater than or equal to 95th centile)

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    End point title
    LGA (greater than or equal to 95th centile)
    End point description
    End point type
    Secondary
    End point timeframe
    Birth
    End point values
    Metformin Standard care
    Number of subjects analysed
    19
    20
    Units: Babies
    1
    2
    No statistical analyses for this end point

    Secondary: LGA (greater than or equal to 4000g)

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    End point title
    LGA (greater than or equal to 4000g)
    End point description
    End point type
    Secondary
    End point timeframe
    Birth
    End point values
    Metformin Standard care
    Number of subjects analysed
    19
    20
    Units: Babies
    3
    1
    No statistical analyses for this end point

    Secondary: Centile

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    End point title
    Centile
    End point description
    End point type
    Secondary
    End point timeframe
    Birth
    End point values
    Metformin Standard care
    Number of subjects analysed
    19
    20
    Units: centile
        median (inter-quartile range (Q1-Q3))
    45.5 (11.7 to 62.1)
    33.95 (11.8 to 48.25)
    No statistical analyses for this end point

    Secondary: NICU admission

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    End point title
    NICU admission
    End point description
    End point type
    Secondary
    End point timeframe
    After birth
    End point values
    Metformin Standard care
    Number of subjects analysed
    19
    20
    Units: Babies
    0
    0
    No statistical analyses for this end point

    Secondary: Shoulder dystocia

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    End point title
    Shoulder dystocia
    End point description
    End point type
    Secondary
    End point timeframe
    After birth
    End point values
    Metformin Standard care
    Number of subjects analysed
    19
    20
    Units: Babies
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The occurrence of adverse events will be sought by non-directive questioning of the patient during the study. Adverse events also may be detected when they are volunteered by the patient.
    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
    Women randomised to the study arm (Metformin only treatment arm) will be prescribed metformin tablets up to 2000mg from randomisation (26-28 weeks gestation) and will stop once they have delivered their baby. Women will be asked to start with 500mg metformin (1 tablet, Once Daily) taken with food, increasing on Day 4 by an increment of 500mg per day (in other words to 1 tablet, twice daily). Day 7: a further increment of 500mg per day (in other words to 1 tablet, three times daily). On Day 14, women will increase the evening dose of metformin by a further 500mg. If side effects (largely anticipated to be gastro-intestinal) are experienced, the woman should drop to the previous dose or 500mg metformin (whichever is the greater) and wait for 3 days before increasing the dosage again. The maximum recommended dose is 2000mg daily, taken as three divided doses. The usual starting dose is one tablet 2 or 3 times daily given during or after meals.

    Reporting group title
    Standard care
    Reporting group description
    In addition to dietary advice and lifestyle advice, women in the standard care arm will be issued with a HBGM meter and asked to record capillary blood glucose before and 1 hour after meals (x 7/day) with target glucose ranges of fasting <5.5 and 1 hour post prandial <7.8mmol/L. Women will be provided with a contact telephone number and asked to contact the research midwife if the blood sugars are outside the target range on 3 or more occasions within one week. The handheld maternity records will be updated to inform health care professionals that the woman is participating in the trial and has been randomised to the standard care arm. A baseline ultrasound to assess fetal growth will be performed at study visit 1. Women will be reviewed in the research clinic 2 weeks after their initial appointment.

    Serious adverse events
    Metformin Standard care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Shoulder dystocia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Metformin Standard care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 20 (5.00%)
    Respiratory, thoracic and mediastinal disorders
    Breathless
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Pregnancy, puerperium and perinatal conditions
    Baby not moving
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Reduced fetal movements
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Generally unwell
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Vomitting
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal cramps
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (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
    19 Oct 2014
    SA01 - TBC - need summary of changes

    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.
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