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    Clinical Trial Results:
    The use of Metformin and Gonadotrophin Releasing Hormone Antagonist for the treatment of women with Polycystic Ovary Syndrome undergoing In-vitro Fertilisation-Embryo Transfer.

    Summary
    EudraCT number
    		 2009-010952-81
    Trial protocol
    		 GB  
    Global end of trial date
    01 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Feb 2018
    First version publication date
    10 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OG08/8802
    Additional study identifiers
    ISRCTN number
    		 ISRCTN21199799
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Leeds Teaching Hospitals NHS Trust
    Sponsor organisation address
    Beckett Street, Leeds, United Kingdom, LS9 7TF
    Public contact
    Doctor Susie Nicholas, Leeds Centre of Reproductive Medicine Seacroft Hospital Leeds LS14 6UH, 0044 1132063111,
    Scientific contact
    Doctor Susie Nicholas, Leeds Centre of Reproductive Medicine Seacroft Hospital Leeds LS14 6UH, 0044 1132063111,
    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
    01 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The prinicpal research objective is to determine if the administration of the drug metformin to women with polycystic ovary syndrome who are undergoing IVF treatment following the short GnRH antagonist treatment protocol reduces the incidence of moderate to severe ovarian hyperstimulation syndrome (OHHS) (i.e. Does metformin reduce the risk of OHSS in this group?).
    Protection of trial subjects
    Monitored during stimulation phase and for OHSS, and live birth outcome.
    Background therapy
    		 Stimulation drugs including Gonal F and puregon and GNRH antagonist( orgalutron/cetrotide).
    Evidence for comparator
    		 Comparing if Metformin reduced risk of OHSS against a placebo. Evidence available that Metformin reduces risk of OHSS in long GNRH agonist. Also has effect on clinical pregnancy rates in IVF treatments. No other medication has same safety profile as this for use in early pregnancy.
    Actual start date of recruitment
    30 Oct 2009
    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: 153
    Worldwide total number of subjects
    153
    EEA total number of subjects
    153
    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)
    153
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 recruited from IVF clinic waiting list between October 2009 and June 2014 (One year where recruitment was paused with change over of principal investigator)

    Pre-assignment
    Screening details
    		 All women on waiting list were screened for inclusion - those eligible fulfilled the Rotterdam criteria plus BMI and age criteria. 169 women were enrolled - 153 started medication . 16 didn't start for a number of reasons including pregnancy, no longer eligible or withdrew consent

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Randomisation by the hospital pharmacy using random permuted blocks method with a 50:50 allocation ratio

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Metformin
    Arm description
    		 Those patients allocated metformin treatment
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule twice a day

    Arm title
    		 Placebo
    Arm description
    		 Those allocated placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule twice a day

    Number of subjects in period 1
    		Metformin Placebo
    Started
    77
    76
    Completed
    77
    76

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 Those patients allocated metformin treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Those allocated placebo

    Reporting group values
    		 Metformin Placebo Total
    Number of subjects
    		 77 76 153
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 77 76 153
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 77 76 153
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Metformin
    Reporting group description
    		 Those patients allocated metformin treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Those allocated placebo

    Primary: Incidence of moderate-severe OHSS with 6 weeks of cycle

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    End point title
    		 Incidence of moderate-severe OHSS with 6 weeks of cycle
    End point description
    End point type
    Primary
    End point timeframe
    6 weeks from starting IVF cycle
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    77
    76
    Units: subjects
    12
    9
    Statistical analysis title
    		 OHSS rate
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 t-test, 1-sided
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 3.49
    Variability estimate
    Standard deviation

    Secondary: Clinical pregnancy rate

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    End point title
    		 Clinical pregnancy rate
    End point description
    When fetal heart beat was seen on 7 week pregnancy ultrasound
    End point type
    Secondary
    End point timeframe
    start of trial to 7 weeks after final treatment date of last patient enrolled
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    77
    76
    Units: pregnancies
        Pregnant
    22
    37
        Not pregnant
    55
    39
    Statistical analysis title
    		 Clinical pregnancy rate
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared corrected
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Number of oocytes collected

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    End point title
    		 Number of oocytes collected
    End point description
    total number of oocytes collected during treatment
    End point type
    Secondary
    End point timeframe
    start of trial to last patient's egg collection
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    77
    76
    Units: egg number
    14
    15
    Statistical analysis title
    		 Oocyte number
    Statistical analysis description
    average number of oocytes per patient
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Number of patients with good day 3 embryos

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    End point title
    		 Number of patients with good day 3 embryos
    End point description
    End point type
    Secondary
    End point timeframe
    start of trial to last clinical treatment of last patient
    End point values
    		 Metformin Placebo
    Number of subjects analysed
    77
    76
    Units: embryo number
        number (not applicable)
    47.1
    52.3
    Statistical analysis title
    		 Good day 3 embryos
    Comparison groups
    Metformin v Placebo
    Number of subjects included in analysis
    153
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Within 6 weeks of starting IVF cycle plus then until birth of child (9 months)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Adverse incidents - OHSS
    Reporting group description
    		 -

    Reporting group title
    Cyst admission
    Reporting group description
    		 those with hospital admission die to cyst

    Serious adverse events
    		 Adverse incidents - OHSS Cyst admission
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 153 (4.58%)
    1 / 153 (0.65%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Reproductive system and breast disorders
    moderate to severe OHSS
         subjects affected / exposed
    7 / 153 (4.58%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    7 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    7 / 153 (4.58%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Adverse incidents - OHSS Cyst admission
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 153 (4.58%)
    0 / 153 (0.00%)
    Reproductive system and breast disorders
    OHSS
         subjects affected / exposed
    7 / 153 (4.58%)
    0 / 153 (0.00%)
         occurrences all number
    7
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Sep 2013
    A number of amendments occurred which involved updating clinical information and protocol

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    09 Jan 2012
    due to change in principal investigator - lapse in recruitment and updating of clinical information
    30 Aug 2012

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    none

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27816925
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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