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    Clinical Trial Results:
    Metformin treatment of pregnant PCOS women and prevention of late miscarriages and preterm birth The PregMet 2 Study

    Summary
    EudraCT number
    		 2011-002203-15
    Trial protocol
    		 NO   SE   IS  
    Global end of trial date
    31 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Aug 2021
    First version publication date
    20 Aug 2021
    Other versions
    Summary report(s)
    		 Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial

    Trial information

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    Trial identification
    Sponsor protocol code
    PregMet2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01587378
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Norwegian University of Science and Technology
    Sponsor organisation address
    Erling Skjalgsons gate 1, Trondheim, Norway, 7491
    Public contact
    Maternity care, Outpatient Unit, Dept. of Obstetrics and Gynecology, St. Olavs Hospital, +47 72575715, Tone.Shetelig.lovvik@stolav.no
    Scientific contact
    Maternity care, Outpatient Unit, Dept. of Obstetrics and Gynecology, St. Olavs Hospital, +47 72575715, Tone.Shetelig.lovvik@stolav.no
    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
    31 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall aim and primary endpoint of the PregMet 2 Study is to investigate whether metformin prevents late miscarriages and preterm deliveries in PCOS women treated with metformin from first trimester of pregnancy to delivery in a large, randomized, controlled, multi-centre trial setting.
    Protection of trial subjects
    Both mothers, fetuses and newborn were closely followed up through pregnancy and 8 weeks postpartum, by specialists in obstetrics, endocrinologists and midwifes. All AE were registered and evaluated continuously. In addition to standard antenatal care the participants had extra glucose controls, ultrasonography of the fetus and easy access to the responsible study investigators.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Aug 2012
    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
    Norway: 390
    Country: Number of subjects enrolled
    Sweden: 46
    Country: Number of subjects enrolled
    Iceland: 51
    Worldwide total number of subjects
    487
    EEA total number of subjects
    487
    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)
    487
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited in Norway (Trondheim, Bergen, Drammen, Tønsberg, Skien, Ålesund, Lillehammer, Bodø), Sweden ( Stockholm, Uppsala, Örebro, Umeå) and Iceland (Reykjavik). First participant included 2012-10-19, last 2016-12-28.

    Pre-assignment
    Screening details
    		 Inclusion criteria: diagnosis of PCOS according to the Rotterdam 2003 criteria, aged 18–45 years, pregnant by any mode of conception with a singleton viable fetus between gestational week 6 and week 12 plus 6 days, had a minimum of 7 days washout of metformin Exclusion criteria diabetes, known liver or kidney failure

    Pre-assignment period milestones
    Number of subjects started
    		 505 [1]
    Number of subjects completed
    		 487

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Physician decision: 5
    Reason: Number of subjects
    		 Protocol deviation: 13
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 18 potential participants were not suitable for inclusion after additional evaluation.
    Period 1
    Period 1 title
    Inclusion 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
    We randomly assigned women (1:1) to receive metformin or placebo via computer-generated random numbers. Randomisation was in blocks of ten for each country and centre. Randomisation of treatment packages was computer generated and was done before inclusion. Randomisation sequence was generated by personnel from the Unit of Applied Clinical Research, none of whom had any involvement in recruitment, assignment, or the rest of the trial. Placebo tablets and metformin tablets were identical.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Metformin
    Arm description
    		 Metformin 500mg tablets, 2 tablets in the morning and 2 tablets in the evening. Taken together with meal.
    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
    500mg x 2 twice daily

    Arm title
    		 Placebo
    Arm description
    		 Identical placebo tablets ( to metformin)
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets twice daily

    Number of subjects in period 1
    		Metformin Placebo
    Started
    244
    243
    Completed
    238
    240
    Not completed
    6
    3
         Physician decision
    2
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    3
    2
    Period 2
    Period 2 title
    Intention to treat end points
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Metformin
    Arm description
    		 -
    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
    500 mg x2 - twice daily

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets twice daily

    Number of subjects in period 2
    		Metformin Placebo
    Started
    238
    240
    Completed
    238
    240

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 Metformin 500mg tablets, 2 tablets in the morning and 2 tablets in the evening. Taken together with meal.

    Reporting group title
    Placebo
    Reporting group description
    		 Identical placebo tablets ( to metformin)

    Reporting group values
    		 Metformin Placebo Total
    Number of subjects
    		 244 243 487
    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 (inter-quartile range (Q1-Q3))
    		 29 (24 to 34) 29 (24 to 36) -
    Gender categorical
    Only women (pregnant)
    Units: Subjects
        Female
    		 244 243 487
        Male
    		 0 0 0
    Ethnicity
    Units: Subjects
        Caucasians
    		 236 220 456
        Non-Caucasians
    		 8 23 31
    Smoking
    Units: Subjects
        Smokers
    		 8 13 21
        Non-smokers
    		 236 230 466
    Mode of conceptio
    Units: Subjects
        spontaneous
    		 111 97 208
        Ovulation induction
    		 49 64 113
        IVF/ICSI
    		 41 49 90
        others
    		 43 33 76
    parity
    Units: Subjects
        0-parous
    		 143 132 275
        multi-parous
    		 101 111 212
    Body mass index
    Units: kg/m2
        median (inter-quartile range (Q1-Q3))
    		 27.5 (18.2 to 36.5) 26.7 (18.8 to 34.6) -
    blood pressure systolic
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 114 (101 to 127) 112 (98 to 127) -
    blood pressure diastolic
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 73 (60 to 86) 71 (58 to 84) -

    End points

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    End points reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 Metformin 500mg tablets, 2 tablets in the morning and 2 tablets in the evening. Taken together with meal.

    Reporting group title
    Placebo
    Reporting group description
    		 Identical placebo tablets ( to metformin)
    Reporting group title
    Metformin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Late miscarriage and preterm delivery

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    End point title
    		 Late miscarriage and preterm delivery
    End point description
    The primary outcome of PregMet2 was the composite incidence of late miscarriage (between week 13 and week 22 and 6 days) and preterm birth (between week 23 and week 36 and 6 days), including spontaneous birth, induced vaginal deliveries, and operative deliveries for medical indications.
    End point type
    Primary
    End point timeframe
    End of pregnancy
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    238
    240
    Units: subjects
        Late miscarriage
    3
    5
        Preterm delivery
    9
    18
        Composite
    12
    23
    Statistical analysis title
    		 Composite endpoint
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.08
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 1.08
    Statistical analysis title
    		 late miscarriage
    Comparison groups
    Placebo v Metformin
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.72
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 3.13
    Statistical analysis title
    		 Preterm delivery
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.11
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 1.16

    Secondary: Hypertension in pregnancy

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    End point title
    		 Hypertension in pregnancy
    End point description
    End point type
    Secondary
    End point timeframe
    During pregnancy
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    238
    240
    Units: subjects
        Hypertension
    16
    13
        No hypertension
    222
    227
    Statistical analysis title
    		 Hypertension in pregnancy
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.57
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 2.94

    Secondary: preeclampsia

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    End point title
    		 preeclampsia
    End point description
    End point type
    Secondary
    End point timeframe
    After gestational week 20
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    238
    240
    Units: subjects
        preeclampsia
    8
    17
        non-preeclampsia
    230
    223
    Attachments
    		 Endpoint table
    Statistical analysis title
    		 Preeclampsia
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 1.15

    Secondary: gestational diabetes

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    End point title
    		 gestational diabetes
    End point description
    End point type
    Secondary
    End point timeframe
    during pregnancy
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    238
    240
    Units: subjects
        gestational diabetes
    60
    57
        no gestational diabetes
    178
    183
    Statistical analysis title
    		 gestational diabetes
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.75
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.66

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inclusion to the study until 8 weeks post partum.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICD
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 Metformin 500mg tablets, 2 tablets in the morning and 2 tablets in the evening. Taken together with meal.

    Reporting group title
    Placebo
    Reporting group description
    		 Identical placebo tablets ( to metformin)

    Serious adverse events
    		 Metformin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 244 (4.10%)
    9 / 243 (3.70%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Pregnancy, puerperium and perinatal conditions
    uterus contractions
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperemesis
         subjects affected / exposed
    2 / 244 (0.82%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 244 (1.64%)
    4 / 243 (1.65%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    pneumonia
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Eating disorder symptom
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Metformin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    90 / 244 (36.89%)
    110 / 243 (45.27%)
    Cardiac disorders
    tachycardia
         subjects affected / exposed
    4 / 244 (1.64%)
    2 / 243 (0.82%)
         occurrences all number
    4
    2
    Pregnancy, puerperium and perinatal conditions
    uterine trauma
         subjects affected / exposed
    3 / 244 (1.23%)
    3 / 243 (1.23%)
         occurrences all number
    3
    3
    Gastrointestinal disorders
    pain, reflux, rectal bleeding
         subjects affected / exposed
    16 / 244 (6.56%)
    24 / 243 (9.88%)
         occurrences all number
    16
    24
    Respiratory, thoracic and mediastinal disorders
    Upper and lower respiratory infections
         subjects affected / exposed
    57 / 244 (23.36%)
    64 / 243 (26.34%)
         occurrences all number
    57
    64
    Musculoskeletal and connective tissue disorders
    pain
         subjects affected / exposed
    10 / 244 (4.10%)
    16 / 243 (6.58%)
         occurrences all number
    10
    16
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 243 (0.41%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Slow inclusion resulting in a longer trial period.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30792154
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