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    Clinical Trial Results:
    Efficacy of Metformin in Pregnant Obese Women, a Randomised Controlled Trial.

    Summary
    EudraCT number
    2009-017134-47
    Trial protocol
    GB  
    Global end of trial date
    30 Apr 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Jul 2020
    First version publication date
    04 Jul 2020
    Other versions
    Summary report(s)
    SAP
    PUBLICATION

    Trial information

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    Trial identification
    Sponsor protocol code
    EMPOWaR
    Additional study identifiers
    ISRCTN number
    ISRCTN51279843
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    CTA Number: 01384/0217/001-0001, UKCRN Ref: 8851, NIHR FUNDER REF: 8/246/09, Scotland A Research Ethics Committee: 10/MRE00/12
    Sponsors
    Sponsor organisation name
    University of Edinburgh
    Sponsor organisation address
    47 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Marise Bucukoglu, University of Edinburgh, marise.bucukoglu@ed.ac.uk
    Scientific contact
    Marise Bucukoglu, University of Edinburgh, marise.bucukoglu@ed.ac.uk
    Sponsor organisation name
    NHS Lothian
    Sponsor organisation address
    47 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Dougla Young, NHS Lothian, douglas.young@luht.scot.nhs.uk
    Scientific contact
    Dougla Young, NHS Lothian, douglas.young@luht.scot.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 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to determine if metformin, administered to obese women during pregnancy, reduces the future life risk of obesity and metabolic syndrome in their babies.
    Protection of trial subjects
    Participants who fulfilled all the potential eligibility criteria and who express an interest in the study had a blood test for renal and liver function and a formal glucose tolerance tests. These tests were performed after consent for the study is signed but before randomisation and women excluded where appropriate.
    Background therapy
    None
    Evidence for comparator
    An intervention with the drug metformin (an insulin sensitizing agent) using a comparator placebo to measure the outcome birthweight centile, a surrogate marker of future life risk of obesity and metabolic syndrome. Obesity causes adverse pregnancy outcomes, with a particular focus on insulin resistance (IR). Metformin reduces insulin resistance and is widely used to treat type II diabetes. Metformin has been shown to be safe during pregnancy and the National Institute for Health and Clinical Excellence (NICE) in the UK now recommends metformin as an alternative to insulin in women with established diabetes in pregnancy. Birthweight centile is an appropriate surrogate marker for the lifetime risk of obesity and metabolic syndrome. Increasing evidence suggests that adult obesity has its origins at or prior to birth, and that intrauterine events leading to high birthweight cause later life obesity.
    Actual start date of recruitment
    01 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 449
    Worldwide total number of subjects
    449
    EEA total number of subjects
    449
    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)
    449
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    449 obese pregnant women in the UK were recruited between 01st Feb 2011 and 16th Jan 2014

    Pre-assignment
    Screening details
    Participants who fulfilled the intial eligibility criteria were sent an invitation letter and if women agreed they were consented to have a blood test. The results of which confirmed eligibiltiy prior to randomisation. Women were excluded, if they were identified with Gestational Diabetes, liver or Kidney disease.

    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, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Blinding was conducted externally by Merck Sante who supplied both the treatments. Unblinding envelopes (emergency or otherwise) were supplied to the local pharmacist. The pharmasist collected the name of the clinician requesting the unblinding, the reasons for it and sent notification of any unblinding to the sponsors.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Metformin
    Arm description
    Metformin (Glucophage) 500mg film-coated tablet (500- 2500mg) maximum tolerated dose.
    Arm type
    Active comparator

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    PL 03759/0012-0013
    Other name
    Glucophage
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Women prescribed metformin tablets up to 2500mg from 12-16 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 in week 2 by an increment of 500mg per day (in other words to 1 tablet, twice daily). Week 3: a further increment of 500mg per day (in other words to 1 tablet, three times daily). In the fourth week the women will increase the evening dose of metformin by a further 500mg and in the fifth week the morning dose will also be increased by a further 500mg.

    Arm title
    Placebo
    Arm description
    Matching Placebo
    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
    500mg up to 2500mg

    Number of subjects in period 1
    Metformin Placebo
    Started
    226
    223
    Completed
    214
    220
    Not completed
    12
    3
         Stillbirth
    2
    -
         miscarriage
    4
    -
         Termination of pregnancy
    1
    2
         Consent withdrawn by subject
    4
    1
         Lost to follow-up
    1
    -

    Baseline characteristics

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

    Reporting group values
    Overall Trial Total
    Number of subjects
    449 449
    Age categorical
    Pregnant women
    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
        arithmetic mean (standard deviation)
    28.7 ± 5.8 -
    Gender categorical
    Pregnant women
    Units: Subjects
        Female
    449 449
        Male
    0 0

    End points

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    End points reporting groups
    Reporting group title
    Metformin
    Reporting group description
    Metformin (Glucophage) 500mg film-coated tablet (500- 2500mg) maximum tolerated dose.

    Reporting group title
    Placebo
    Reporting group description
    Matching Placebo

    Primary: Z score of birthweight percentile

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    End point title
    Z score of birthweight percentile
    End point description
    End point type
    Primary
    End point timeframe
    Birth
    End point values
    Metformin Placebo
    Number of subjects analysed
    214
    220
    Units: g
        arithmetic mean (standard deviation)
    0.2664 ± 1.0179
    0.2680 ± 1.0055
    Statistical analysis title
    BirthWeight Centile
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    434
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    < 0.05
    Method
    t-test, 2-sided
    Confidence interval
    Notes
    [1] - Intention to Treat

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All AEs and SAEs were recorded from the time a participant was randomised until after the last baby is born and discharged from hospital or the end of the postnatal period (28 days after the birth), which ever is sooner.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Not collected. AEs recorded in participant notes only.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2010
    Additional information provided to the MHRA who considered this an amended request for CTA.
    20 Sep 2010
    Protocol modified Version 2 Expanded details about the substudies PIL and consent forms amended
    13 Apr 2011
    Table of study assessments - errors corrected 1 hour GTT blood sample removed from visits Para 6.1 additional text added
    30 Sep 2011
    Change to reference range for entry liver function test clarification re exclusion criteria for GDM - in future relate just to WHO and not SIGN guidelines
    01 Sep 2012
    Revision to the protocol for clarifications and addition of new sub study.
    30 Sep 2013
    Para 6.4 amendment and additional documents created for Qualitative interviews
    10 Mar 2014
    Para 6.4 and 9.11 updated to include payment for participants and inclusion of women as controls for a vascular function, sub study.
    24 Sep 2014
    Updated protocol for clarification of outcomes to harmonise with statistical analysis plan Removal of sub-studies to which subjects were not recruited

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26165398
    http://www.ncbi.nlm.nih.gov/pubmed/27606384
    http://www.ncbi.nlm.nih.gov/pubmed/25588785
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