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    Clinical Trial Results:
    A prospective, randomized, double-blind parallel-arm, placebo-controlled study to assess the effects on ovarian activity of a combined oral contraceptive pill when preceded by the intake of ellaOne® (ulipristal acetate 30 mg) or placebo

    Summary
    EudraCT number
    		 2011-005573-23
    Trial protocol
    		 SE   NL   GB  
    Global end of trial date
    31 Aug 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2914-015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Laboratoire HRA Pharma
    Sponsor organisation address
    15 rue Béranger, Paris, France, 75003
    Public contact
    Medical Affairs department, Laboratoire HRA Pharma, 0033 140331130, d.levy@hra-pharma.com
    Scientific contact
    Medical Affairs department, Laboratoire HRA Pharma, 0033 140331130, d.levy@hra-pharma.com
    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
    11 Feb 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to compare the effects of quick starting a Combined Oral Contraceptive Pill (COCP) on follicular growth and hormonal parameters after ellaOne® or placebo intake.
    Protection of trial subjects
    This trial was conducted in accordance with the GCPs guidelines, ethical principles of the Declaration of Helsinki and local applicable regulatory requirement(s). Additionally, it was conducted by scientifically and medically qualified persons who respected the rights and welfare of the subjects and after the protocol was approved by Ethics Committee in each country.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Mar 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
    Netherlands: 45
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    United Kingdom: 18
    Worldwide total number of subjects
    76
    EEA total number of subjects
    76
    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)
    76
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from 3 study sites in the UK, Sweden and the Netherlands. The recruitement period started on 26 March 2012 and ended on 27 July 2012

    Pre-assignment
    Screening details
    		 103 subjects were screened (26, 21, 56 in UK, Sweden and Netherlands respectively). 27 subjects dropped out before inclusion for the following reasons: non respect of inclusion/exclusion criteria; ovary or follicle not visible or TVU couldn't be performed; subject not available for further visits; subject lost to FU; ICF withdrawal.

    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, Data analyst, Carer, Assessor
    Blinding implementation details
    Treatment were delivered to eligible subjects in the ascending order of boxes numbers. A randomization schedule linking treatment numbers to treatment codes (ellaOne or Placebo) was generated by independent statistician but was not provided to sites. The sites only received the sealed envelopes corresponding to each treatment number that was sent to them.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ellaOne
    Arm description
    		 Intake of 1 pill of ellaOne on the day of inclusion, followed by a daily intake of 1 tablet of Microgynon 30 (combined oral contraceptive pill (COCP)) for 21 consecutive days, starting on the day after ellaOne intake
    Arm type
    		 Experimental

    Investigational medicinal product name
    ellaOne
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet containing 30 mg micronized UPA was administered on site to women with water

    Investigational medicinal product name
    Microgynon 30
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet containing 30 µg ethinyl estradiol / 150 µg levonorgestrel was taken daily for 21 consecutive days, at approximately the same time every day

    Arm title
    		 Placebo
    Arm description
    		 Intake of 1 pill of Placebo on the day of inclusion, followed by a daily intake of 1 tablet of Microgynon 30 for 21 consecutive days, starting on the day after Placebo intake
    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
    1 tablet of Placebo was administered on site to women with water

    Investigational medicinal product name
    Microgynon 30
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet containing 30 µg ethinyl estradiol / 150 µg levonorgestrel was taken daily for 21 consecutive days, at approximately the same time every day

    Number of subjects in period 1
    		ellaOne Placebo
    Started
    39
    37
    Completed
    39
    37

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ellaOne
    Reporting group description
    		 Intake of 1 pill of ellaOne on the day of inclusion, followed by a daily intake of 1 tablet of Microgynon 30 (combined oral contraceptive pill (COCP)) for 21 consecutive days, starting on the day after ellaOne intake

    Reporting group title
    Placebo
    Reporting group description
    		 Intake of 1 pill of Placebo on the day of inclusion, followed by a daily intake of 1 tablet of Microgynon 30 for 21 consecutive days, starting on the day after Placebo intake

    Reporting group values
    		 ellaOne Placebo Total
    Number of subjects
    		 39 37 76
    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
        Adults (18-64 years)
    		 39 37 76
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 23.5 ( 2.7 ) 24.1 ( 3.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 39 37 76
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    ellaOne
    Reporting group description
    		 Intake of 1 pill of ellaOne on the day of inclusion, followed by a daily intake of 1 tablet of Microgynon 30 (combined oral contraceptive pill (COCP)) for 21 consecutive days, starting on the day after ellaOne intake

    Reporting group title
    Placebo
    Reporting group description
    		 Intake of 1 pill of Placebo on the day of inclusion, followed by a daily intake of 1 tablet of Microgynon 30 for 21 consecutive days, starting on the day after Placebo intake

    Subject analysis set title
    Full Analysis Set population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized and treated subjects for whom at least one assessment of the main criterion (Hoogland score) is available

    Subject analysis set title
    Per protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomized and treated subjects who completed the study without any major violations of the protocol

    Subject analysis set title
    Specificity population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects of the FAS population that had a follicle size ≤18mm at time of treatment initiation

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    A ll randomized and treated subjects that have received at least one dose of the study treatment, irrespective of satisfying other criteria

    Primary: Follicle status at end of treatment period in FAS population

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    End point title
    		 Follicle status at end of treatment period in FAS population
    End point description
    Quiescence was considered as reached when the Hoogland score was ≤ 3, ovulation when the score was 6. The other possible follicle status were Luteinized Unruptured Follicle (LUF) or persistent follicle.
    End point type
    Primary
    End point timeframe
    Follicular growth was measured (transvaginal ultrasounds TVU) at each subject visit on site (i.e. every 2 to 3 days), up to follicular size <= 13 mm at 2 consecutive visits.
    End point values
    		 ellaOne Placebo
    Number of subjects analysed
    39
    37
    Units: Subjects
        Quiescence
    24
    23
        Ovulation
    13
    12
        LUF
    2
    1
        Persistent follicle
    0
    1
    Statistical analysis title
    		 Effect of treatment - quiescence
    Statistical analysis description
    Competing risk survival analysis - A Fine and Gray model was used in which treatment, dominant follicular size at inclusion, cycle day at inclusion and previous method of contraception were the explaining variables.
    Comparison groups
    ellaOne v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.2089
    Method
    		 Competing risk analysis
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.702
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.404
         upper limit
    		 1.219
    Statistical analysis title
    		 Effect of follicle size - quiescence
    Statistical analysis description
    Competing risk survival analysis - A Fine and Gray model was used in which treatment, dominant follicular size at inclusion, cycle day at inclusion and previous method of contraception were the explaining variables.
    Comparison groups
    ellaOne v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.0061
    Method
    		 Competing risk analysis
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.696
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.538
         upper limit
    		 0.902
    Statistical analysis title
    		 Effect of treatment - ovulation
    Statistical analysis description
    Competing risk survival analysis - A Fine and Gray model was used in which treatment, dominant follicular size at inclusion, cycle day at inclusion and previous method of contraception were the explaining variables.
    Comparison groups
    ellaOne v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.2376
    Method
    		 Competing risk analysis
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.769
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.686
         upper limit
    		 4.56
    Statistical analysis title
    		 Effect of follicle size - ovulation
    Statistical analysis description
    Competing risk survival analysis - A Fine and Gray model was used in which treatment, dominant follicular size at inclusion, cycle day at inclusion and previous method of contraception were the explaining variables.
    Comparison groups
    ellaOne v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.0024
    Method
    		 Competing risk analysis
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.186
         upper limit
    		 2.212

    Secondary: Time to quiescence in FAS population

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    End point title
    		 Time to quiescence in FAS population
    End point description
    Time from treatment initiation to Hoogland score ≤ 3
    End point type
    Secondary
    End point timeframe
    Follicular growth was measured by transvaginal ultrasounds (TVU) at each subject visit on site (i.e. every 2 to 3 days), up to follicular size <= 13 mm at 2 consecutive visits; Quiescence was defined as Hoogland score (HS) <=3
    End point values
    		 ellaOne Placebo
    Number of subjects analysed
    24
    23
    Units: percentage of subjects
    number (not applicable)
        Day 7 of COCP
    70.8
    60.9
        Day 14 of COCP
    100
    100
    No statistical analyses for this end point

    Secondary: Time to ovulation in FAS population

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    End point title
    		 Time to ovulation in FAS population
    End point description
    Time from treatment initiation to Hoogland score = 6
    End point type
    Secondary
    End point timeframe
    Measure of follicle growth was done at each visit on site, i.e. every 2 or 3 days.
    End point values
    		 ellaOne Placebo
    Number of subjects analysed
    13
    12
    Units: Percentage of subjects
    number (not applicable)
        Ovulation on COCP day 4
    15.4
    50
        Ovulation on COCP day 6
    76.9
    91.7
        Ovulation on COCP day 7
    76.9
    100
        Ovulation on COCP day 11
    100
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the end of study visit regardless of seriousness or relationship to investigational product. Analysis was performed on safety population.
    Adverse event reporting additional description
    Headache was the most frequently reported adverse event that was judged to be possibly related to both ellaOne®/placebo and COCP intake
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    ellaOne
    Reporting group description
    		 Intake of 1 pill of 30mg ellaOne on the day of inclusion, followed by a daily intake of 1 tablet of Microgynon 30 for 21 consecutive days, starting on the day after ellaOne intake

    Reporting group title
    Placebo
    Reporting group description
    		 Intake of 1 pill of Placebo on the day of inclusion, followed by a daily intake of 1 tablet of Microgynon 30 for 21 consecutive days, starting on the day after Placebo intake

    Serious adverse events
    		 ellaOne Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 37 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 ellaOne Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 39 (66.67%)
    23 / 37 (62.16%)
    Nervous system disorders
    headache
    Additional description: Headache was the most frequently reported adverse event that was judged to be possibly related to both ellaOne®/placebo and COCP intake
         subjects affected / exposed
    9 / 39 (23.08%)
    9 / 37 (24.32%)
         occurrences all number
    14
    10
    Gastrointestinal disorders
    Abdominal pain lower
    Additional description: Abdominal pain lower was the second most frequently reported adverse event that was judged to be possibly related to both ellaOne®/placebo and COCP intake
         subjects affected / exposed
    6 / 39 (15.38%)
    1 / 37 (2.70%)
         occurrences all number
    7
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 39 (10.26%)
    5 / 37 (13.51%)
         occurrences all number
    4
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jan 2012
    This amendement was written on request of the Netherlands Ethics committe. The following updates were done: the size of each treatment arm was specified in section ‘sample size justification’; The declaration of Helsinki in Appendix A was updated.

    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/25994664
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