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    Clinical Trial Results:
    Liraglutide in PCOS (LIPOS) Study: Evaluation of the Efficacy of Liraglutide on Menstrual Cyclicity in Women with PCOS - a prospective randomised double-blind placebo-controlled study

    Summary
    EudraCT number
    		 2012-002073-60
    Trial protocol
    		 GB  
    Global end of trial date
    15 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Oct 2017
    First version publication date
    27 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    REGO-2012-011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1126-3292
    Sponsors
    Sponsor organisation name
    Warwick Medical School
    Sponsor organisation address
    Gibbet Hill Road, Coventry, United Kingdom, CV4 7AL
    Public contact
    LIPOS study team, Warwick Medical School, LIPOS@warwick.ac.uk
    Scientific contact
    LIPOS study team, Warwick Medical School, LIPOS@warwick.ac.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
    24 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to investigate whether adding liraglutide (at a maximum dose of 1.8 mg once daily) to metformin (at a maximum dose of 1000 mg twice daily) for 48 weeks of treatment has a significant benefit in improving the regularity of periods (menstruation) in PCOS women.
    Protection of trial subjects
    The study was approved by a Research Ethics Committee and received authorisation from the Medicines and Healthcare Products Regulatory Authority. Patients received verbal and written information prior to consenting to the trial and had the time to consider their participation and opportunity to ask questions. Patient data were anonymised to ensure information was kept confidential. Identifiable information was kept separately in a secure location
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 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
    United Kingdom: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    80
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from local PCOS clinics

    Pre-assignment
    Screening details
    		 496 patients were screened for eligibility, with 105 patients consented and registered with the study. Registered patients were prescribed metformin and followed up for four weeks before being randomized into the study.

    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
    		 Investigator, Monitor, Data analyst, Carer, Assessor, Subject
    Blinding implementation details
    Placebo injections were used to blind medication use. The participant, clinical team and data analyst were blinded to treatment arm. A remote randomisation service independent from the trial management team was used to conceal allocation. Data which could un-blind treatment arm was not analysed until data collection was complete

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Liraglutide arm
    Arm description
    		 Liraglutide and metformin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Starting dose for liraglutide is 0.6 mg once daily. Daily dose of liraglutide is increased by a dose level increment of 0.6 mg every 7 days, until maintenance dose of 1.8 mg once daily has been achieved. Dose remains at 1.2mg if maintenance level not tolerated.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The starting dose of Glucophage SR was 500mg once daily, titrated weekly over four weeks to a maintenance dose of 1,000mg twice daily. If 1,000mg twice daily was not tolerated, then the maximum dosage tolerated was maintained.

    Arm title
    		 Control arm
    Arm description
    		 Placebo injection and metformin
    Arm type
    		 Placebo

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The usual starting dose is one tablet of Glucophage SR 1,000 mg twice daily. If 1,000mg twice daily was not tolerated, then the maximum dosage tolerated was maintained.

    Number of subjects in period 1
    		Liraglutide arm Control arm
    Started
    39
    41
    Completed
    24
    27
    Not completed
    15
    14
         Consent withdrawn by subject
    6
    2
         Pregnancy
    2
    5
         Lost to follow-up
    6
    7
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Liraglutide arm
    Reporting group description
    		 Liraglutide and metformin

    Reporting group title
    Control arm
    Reporting group description
    		 Placebo injection and metformin

    Reporting group values
    		 Liraglutide arm Control arm Total
    Number of subjects
    		 39 41 80
    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)
    		 39 41 80
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Participant age at randomization
    Units: years
        arithmetic mean (standard deviation)
    		 29.8 ( 6.7 ) 31 ( 7.5 ) -
    Gender categorical
    Participant gender
    Units: Subjects
        Female
    		 39 41 80
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Liraglutide arm
    Reporting group description
    		 Liraglutide and metformin

    Reporting group title
    Control arm
    Reporting group description
    		 Placebo injection and metformin

    Subject analysis set title
    Completed follow up - liraglutide arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were randomized to the liraglutide arm, completed all 48 weeks of follow up and returned at least one month of diary data.

    Subject analysis set title
    Completed follow up - control arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were randomized to the control arm, completed all 48 weeks of follow up and returned at least one month of diary data.

    Primary: Median number of menstrual cycles per participant during intervention

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    End point title
    		 Median number of menstrual cycles per participant during intervention
    End point description
    Median number of menstrual cycles per participant during study follow up: A menstrual cycle is defined as at least two consecutive days of bleeding separated by 14 or more days. At least one day of bleeding must be heavier than spotting. Women who withdraw from the trial due to pregnancy will have experienced ovulation and hence have a “masked” period during follow up. This will be estimated by assigning day 0 of the pregnancy (as approximated by the pregnancy dating scan) as the last observed period. To be entered into the analysis, participants must also have returned at least one month of diary data.
    End point type
    Primary
    End point timeframe
    48 weeks after randomization
    End point values
    		 Liraglutide arm Control arm Completed follow up - liraglutide arm Completed follow up - control arm
    Number of subjects analysed
    30 [1]
    37 [2]
    20 [3]
    27 [4]
    Units: Menstrual periods
    7
    4
    8
    7
    Notes
    [1] - No. of women who returned diary data
    [2] - No. of women who returned diary data
    [3] - No. of women who returned diary data
    [4] - No. of women who returned diary data
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The number of menstrual cycles will be modelled by a Poisson regression model with the addition of a single binary variable denoting treatment group and an offset term denoting time in follow up.
    Comparison groups
    Liraglutide arm v Control arm
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07
    Method
    		 Poisson regression model
    Parameter type
    		 Rate ratio
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.71
    Statistical analysis title
    		 Completed follow-up
    Comparison groups
    Completed follow up - control arm v Completed follow up - liraglutide arm
    Number of subjects included in analysis
    47
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.01
    Method
    		 Poisson regression
    Parameter type
    		 Rate ratio
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.07
         upper limit
    		 1.91
    Notes
    [5] - Sensitivity analysis of the primary analysis, restricting the data to those 47 women who completed follow-up

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation to end of follow up (56 weeks)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Liraglutide arm
    Reporting group description
    		 Liraglutide and metformin

    Reporting group title
    Control arm
    Reporting group description
    		 Placebo injection and metformin

    Serious adverse events
    		 Liraglutide arm Control arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 41 (4.88%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Gallbladder enlargement
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tonsillitis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 41 (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: 2%
    Non-serious adverse events
    		 Liraglutide arm Control arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 41 (2.44%)
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 41 (2.44%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Mar 2013
    Diagnosis criteria changed to PCOS based 2/3 of Rotterdam criteria, instead of 3/3.
    07 Oct 2013
    1) R&D/SSI: Expansion of recruitment sites to include local GP practices. 2) Design and display of a poster for display at PCOS clinics and GP surgeries. 3) Inclusion criteria amended: - Upper age limitation removed; replaced with ‘pre-menopausal’ - Upper BMI limitation removed - Non-smoking requirement removed - Restrictions based on IGT testing removed
    25 Feb 2014
    Condensed Patient Information Sheet
    13 Aug 2014
    Reduced number of women to be recruited; amended visit schedule to be fewer visits and to allow home pregnancy testing
    14 Nov 2014
    1) Amendment to protocol (section on power calculation amended, inclusion of Bodpod assessments for body composition) 2) Changes to Patient Information Scheet (to include Bodpod, undesirable effects, minor corrections) 3) Extension of end date to 31/03/16
    17 Jul 2015
    1) New document: end-of-study letter (thanking participants; stating what happens to their care and how to access study results. Enclosing shopping voucher) 2) Approval for use of shopping vouchers as reward for patients who have completed the study
    11 Aug 2016
    1) Amendment to protocol (clarifications withdrawal process, EudraCT number included, updated statistical analysis plan and changed study windows). 2) New documents: follow up letter template, template text messages, email to participants and letter to employer.

    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.
    84% of the participants returned evaluable primary outcome data. There were participants who did not return data for the whole of the follow up. There was a higher than expected rate of loss to follow up. The initial targeted power was not achieved.
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