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    Clinical Trial Results:
    Multi-center, single-arm study to assess the safety, efficacy, discontinuation rate and pharmacokinetics of the low-dose levonorgestrel intrauterine contraceptive system (LCS12) in post-menarcheal female adolescents under 18 years of age for 1 year, and an optional 2-year extension phase

    Summary
    EudraCT number
    		 2011-002065-37
    Trial protocol
    		 SE   FI   NL   AT   BE   DE   DK   NO  
    Global end of trial date
    28 May 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    04 Sep 2016
    First version publication date
    02 Jul 2016
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    Bayer sponsor contact information to be updated

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY86-5028/14371
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01434160
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368, Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000606-PIP01-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the safety of the low-dose levonorgestrel (LNG) (12 microgram [mcg]/24 hour [h]) intrauterine contraceptive system (LCS12) in adolescents over 1 year of treatment, including the insertion and removal procedures. The objective of the 2-year extension phase was to evaluate safety and efficacy of LCS12 during the intended duration of use, that is, for up to 3 years.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects and/or their legally authorized representatives. Participating subjects and/or their legally authorized representatives signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Sep 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 64
    Country: Number of subjects enrolled
    Germany: 64
    Country: Number of subjects enrolled
    Austria: 63
    Country: Number of subjects enrolled
    Denmark: 17
    Country: Number of subjects enrolled
    Finland: 23
    Country: Number of subjects enrolled
    Netherlands: 55
    Country: Number of subjects enrolled
    Norway: 4
    Country: Number of subjects enrolled
    Sweden: 14
    Worldwide total number of subjects
    304
    EEA total number of subjects
    304
    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)
    302
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 36 study centers for 1 year treatment phase and 34 study centers for 2 year extension phase in 8 countries, from 26 September 2011 (first subject first visit) to 28 May 2015 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall 343 subjects were enrolled in the study, of which 304 were assigned to treatment. Thirty nine (39) subjects were excluded at screening, of which 26 were screening failures, 5 were withdrew consent, 4 were lost to follow-up, 2 due to adverse events, and 2 for other reasons.

    Period 1
    Period 1 title
    Treatment Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Levonorgestrel (BAY86-5028)
    Arm description
    		 Subjects received levonorgestrel (LNG) intrauterine contraceptive system with an initial in vitro release rate of 12 microgram LNG/day (LCS12) for up to 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levonorgestrel
    Investigational medicinal product code
    BAY86-5028
    Other name
    Pharmaceutical forms
    Intrauterine delivery system
    Routes of administration
    Intrauterine use
    Dosage and administration details
    The total LNG content in LCS12 was 13.5 mg. LCS12 was inserted into the uterus and could remain in place for up to 12 months.

    Number of subjects in period 1
    		Levonorgestrel (BAY86-5028)
    Started
    304
    Completed
    253
    Not completed
    51
         Insertion failure
    1
         Adverse event, non-fatal
    40
         Protocol violation
    2
         Death
    1
         Other, unspecified
    4
         Lost to follow-up
    3
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Levonorgestrel (BAY86-5028)
    Arm description
    		 Subjects received LCS12 for 12 months with an optional extension phase for further 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levonorgestrel
    Investigational medicinal product code
    BAY86-5028
    Other name
    Pharmaceutical forms
    Intrauterine delivery system
    Routes of administration
    Intrauterine use
    Dosage and administration details
    Subjects received LCS12 for 12 months with an optional extension phase for further 24 months.

    Number of subjects in period 2
    		Levonorgestrel (BAY86-5028)
    Started
    220
    Completed
    173
    Not completed
    47
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    25
         Protocol violation
    1
         Wish for pregnancy
    3
         Other, unspecified
    14
         Pregnancy
    1
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Phase
    Reporting group description
    		 Subjects received LCS12 for 12 months with optional extension of 24 months.

    Reporting group values
    		 Treatment Phase Total
    Number of subjects
    		 304 304
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 16.2 ( 1 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 304 304
        Male
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    Levonorgestrel (BAY86-5028)
    Reporting group description
    		 Subjects received levonorgestrel (LNG) intrauterine contraceptive system with an initial in vitro release rate of 12 microgram LNG/day (LCS12) for up to 12 months.
    Reporting group title
    Levonorgestrel (BAY86-5028)
    Reporting group description
    		 Subjects received LCS12 for 12 months with an optional extension phase for further 24 months.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS included all subjects who had the LCS12 inserted or had at least an insertion attempt (successful or unsuccessful).

    Primary: Percentage of Subjects With Treatment-Emergent Adverse Events During Treatment Phase

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Adverse Events During Treatment Phase [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An /serious adverse events (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse events were defined as AEs/SAEs that started or worsened after the study drug treatment.
    End point type
    Primary
    End point timeframe
    From the start of study treatment up to 12 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    304 [2]
    Units: Percentage of subjects
    number (not applicable)
        TEAE
    82.6
        TESAE
    7.6
    Notes
    [2] - FAS
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Treatment-Emergent Adverse Events During Overall Study

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Adverse Events During Overall Study [3]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An /serious adverse events (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse events were defined as AEs/SAEs that started or worsened after the study drug treatment.
    End point type
    Primary
    End point timeframe
    From start of study treatment until 36 months (end of extension phase)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    304 [4]
    Units: Percentage of subjects
    number (not applicable)
        TEAE
    87.8
        TESAE
    11.2
    Notes
    [4] - FAS
    No statistical analyses for this end point

    Secondary: Overall Satisfaction Rating by the 5-Point Likert Item at Month 12

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    End point title
    		 Overall Satisfaction Rating by the 5-Point Likert Item at Month 12
    End point description
    Satisfaction was assessed by the subject based on a 5-point Likert item, using the following question: How satisfied are you with the birth control method used during the study? and the answers were any of the following: 1. Very satisfied 2. Satisfied 3. Neither satisfied nor dissatisfied 4. Dissatisfied 5. Very dissatisfied. The overall satisfaction rate was the percentage of subjects selecting “1. Very satisfied” or “2. Satisfied” for the above question.
    End point type
    Secondary
    End point timeframe
    At Month 12
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    304 [5]
    Units: Subjects
        Missing
    10
        Very Satisfied
    163
        Satisfied
    92
        Neither satisfied nor dissatisfied
    17
        Dissatisfied
    19
        Very Dissatisfied
    3
    Notes
    [5] - FAS
    No statistical analyses for this end point

    Secondary: Contraceptive Efficacy - Pearl Index

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    End point title
    		 Contraceptive Efficacy - Pearl Index
    End point description
    The pearl index was defined as the number of pregnancies per 100 woman years. The following PIs were calculated: First year PI, Second year PI, Third year PI, 2-year PI, 3-year PI and Overall PI. Given the assumption that the number of pregnancies follows a Poisson distribution, the Pearl Index thus is the mean of this distribution. In the table below, "n" signifies the number of subjects evaluable at the corresponding time points.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to 3 years
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    304 [6]
    Units: pregnancies per 100 woman years
    number (confidence interval 95%)
        Year 1 (n = 304)
    0 (0 to 1.88)
        Year 2 (n = 234)
    0.47 (0.01 to 2.62)
        Year 3 (n = 205)
    0.56 (0.01 to 3.1)
        2 year (n = 304)
    0.24 (0.01 to 1.36)
        3 year (n = 304)
    0.34 (0.04 to 1.23)
        Overall (n = 304)
    0.34 (0.04 to 1.23)
    Notes
    [6] - FAS
    No statistical analyses for this end point

    Secondary: Bleeding Patterns in Days by 28-day Reference Periods - Reference Period 1

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    End point title
    		 Bleeding Patterns in Days by 28-day Reference Periods - Reference Period 1
    End point description
    The occurrence of vaginal bleeding was recorded by study subjects every day in an e-diary. Bleeding intensity was categorized as: no vaginal bleeding, spotting (less than associated with normal menstruation relative to the subject’s experience with no need for sanitary protection except for panty liners), light (less than associated with normal menstruation relative to the subject’s experience with need for sanitary protection), normal (similar to normal menstruation relative to the subject’s experience) and heavy (more than normal menstruation relative to the subject’s experience). Spotting episode (SE) means day(s) with bleeding/spotting preceded and followed by at least 2 bleeding-free days. Spotting only episodes (SOE) means day(s) with spotting preceded and followed by at least 2 bleeding-free days and Bleeding/spotting-free interval means at least 2 days without bleeding/spotting preceded and followed by at least 1 bleeding/spotting day.
    End point type
    Secondary
    End point timeframe
    At reference period 1 (1 reference period=28-days) during 1-year treatment phase
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    141 [7]
    Units: subjects
        at least 1 bleeding/spotting day
    141
        at least 1 bleeding day (excluding spotting)
    137
        at least 1 bleeding/spotting or SOE
    113
        at least 1 bleeding/SE (excluding SOE)
    113
    Notes
    [7] - FAS with evaluable subjects for this outcome
    No statistical analyses for this end point

    Secondary: Bleeding Patterns in Days by 28-day Reference Periods - Reference Period 5

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    End point title
    		 Bleeding Patterns in Days by 28-day Reference Periods - Reference Period 5
    End point description
    The occurrence of vaginal bleeding was to be recorded by study subjects every day in an e-diary. Bleeding intensity was categorized as: no vaginal bleeding, spotting (less than associated with normal menstruation relative to the subject’s experience with no need for sanitary protection except for panty liners), light (less than associated with normal menstruation relative to the subject’s experience with need for sanitary protection), normal (similar to normal menstruation relative to the subject’s experience) and heavy (more than normal menstruation relative to the subject’s experience). For Bleeding/spotting-free interval at least 2 days without bleeding/spotting preceded and followed by at least 1 bleeding/spotting day. For Spotting-only episode day(s) with spotting preceded and followed by at least 2 bleeding-free days and for Bleeding/spotting episode Day(s) with bleeding/spotting preceded and followed by at least 2 bleeding-free days.
    End point type
    Secondary
    End point timeframe
    At reference period 5 (1 reference period=28-days) during 1-year treatment phase
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    74 [8]
    Units: subjects
        at least 1 bleeding/spotting day
    64
        at least 1 bleeding day (excluding spotting)
    49
        at least 1 bleeding/spotting or SOE
    59
        at least 1 bleeding/SE (excluding SOE)
    59
    Notes
    [8] - FAS with evaluable subjects for this outcome
    No statistical analyses for this end point

    Secondary: Bleeding Patterns in Days by 28-day Reference Periods - Reference Period 9

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    End point title
    		 Bleeding Patterns in Days by 28-day Reference Periods - Reference Period 9
    End point description
    The occurrence of vaginal bleeding was to be recorded by study subjects every day in an e-diary. Bleeding intensity was categorized as: no vaginal bleeding, spotting (less than associated with normal menstruation relative to the subject’s experience with no need for sanitary protection except for panty liners), light (less than associated with normal menstruation relative to the subject’s experience with need for sanitary protection), normal (similar to normal menstruation relative to the subject’s experience) and heavy (more than normal menstruation relative to the subject’s experience). For Bleeding/spotting-free interval at least 2 days without bleeding/spotting preceded and followed by at least 1 bleeding/spotting day. For Spotting-only episode day(s) with spotting preceded and followed by at least 2 bleeding-free days and for Bleeding/spotting episode Day(s) with bleeding/spotting preceded and followed by at least 2 bleeding-free days.
    End point type
    Secondary
    End point timeframe
    At reference period 9 (1 reference period=28-days) during 1-year treatment phase
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    56 [9]
    Units: subjects
        at least 1 bleeding/spotting day
    49
        at least 1 bleeding day (excluding spotting)
    35
        at least 1 bleeding/spotting or SOE
    49
        at least 1 bleeding/SE (excluding SOE)
    49
    Notes
    [9] - FAS with evaluable subjects for this outcome
    No statistical analyses for this end point

    Secondary: Bleeding Patterns in Days by 28-day Reference Periods - Reference Period 13

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    End point title
    		 Bleeding Patterns in Days by 28-day Reference Periods - Reference Period 13
    End point description
    The occurrence of vaginal bleeding was to be recorded by study subjects every day in an e-diary. Bleeding intensity was categorized as: no vaginal bleeding, spotting (less than associated with normal menstruation relative to the subject’s experience with no need for sanitary protection except for panty liners), light (less than associated with normal menstruation relative to the subject’s experience with need for sanitary protection), normal (similar to normal menstruation relative to the subject’s experience) and heavy (more than normal menstruation relative to the subject’s experience). For Bleeding/spotting-free interval at least 2 days without bleeding/spotting preceded and followed by at least 1 bleeding/spotting day. For Spotting-only episode day(s) with spotting preceded and followed by at least 2 bleeding-free days and for Bleeding/spotting episode Day(s) with bleeding/spotting preceded and followed by at least 2 bleeding-free days.
    End point type
    Secondary
    End point timeframe
    At reference period 13 (1 reference period=28-days) during 1-year treatment phase
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    36 [10]
    Units: subjects
        at least 1 bleeding/spotting day
    29
        at least 1 bleeding day (excluding spotting)
    23
        at least 1 bleeding/spotting or SOE
    28
        at least 1 bleeding/SE (excluding SOE)
    28
    Notes
    [10] - FAS with evaluable subjects for this outcome
    No statistical analyses for this end point

    Secondary: Bleeding Patterns in Days by 90-day Reference Periods - Reference Period 1

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    End point title
    		 Bleeding Patterns in Days by 90-day Reference Periods - Reference Period 1
    End point description
    The occurrence of vaginal bleeding was to be recorded by study subjects every day in an e-diary. Bleeding intensity was categorized as: no vaginal bleeding, spotting (less than associated with normal menstruation relative to the subject’s experience with no need for sanitary protection except for panty liners), light (less than associated with normal menstruation relative to the subject’s experience with need for sanitary protection), normal (similar to normal menstruation relative to the subject’s experience) and heavy (more than normal menstruation relative to the subject’s experience). For Bleeding/spotting-free interval at least 2 days without bleeding/spotting preceded and followed by at least 1 bleeding/spotting day. For Spotting-only episode day(s) with spotting preceded and followed by at least 2 bleeding-free days and for Bleeding/spotting episode Day(s) with bleeding/spotting preceded and followed by at least 2 bleeding-free days.
    End point type
    Secondary
    End point timeframe
    At reference period 1 (1 reference period=90-days) during 1-year treatment phase
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    76 [11]
    Units: subjects
        at least 1 bleeding/spotting day
    76
        at least 1 bleeding day (excluding spotting)
    74
        at least 1 bleeding/spotting or SOE
    73
        at least 1 bleeding/SE (excluding SOE)
    73
    Notes
    [11] - FAS with evaluable subjects for this outcome
    No statistical analyses for this end point

    Secondary: Bleeding Patterns in Days by 90-day Reference Periods - Reference Period 2

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    End point title
    		 Bleeding Patterns in Days by 90-day Reference Periods - Reference Period 2
    End point description
    The occurrence of vaginal bleeding was to be recorded by study subjects every day in an e-diary. Bleeding intensity was categorized as: no vaginal bleeding, spotting (less than associated with normal menstruation relative to the subject’s experience with no need for sanitary protection except for panty liners), light (less than associated with normal menstruation relative to the subject’s experience with need for sanitary protection), normal (similar to normal menstruation relative to the subject’s experience) and heavy (more than normal menstruation relative to the subject’s experience). For Bleeding/spotting-free interval at least 2 days without bleeding/spotting preceded and followed by at least 1 bleeding/spotting day. For Spotting-only episode day(s) with spotting preceded and followed by at least 2 bleeding-free days and for Bleeding/spotting episode Day(s) with bleeding/spotting preceded and followed by at least 2 bleeding-free days.
    End point type
    Secondary
    End point timeframe
    At reference period 2 (1 reference period=90-days) during 1-year treatment phase
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    45 [12]
    Units: subjects
        at least 1 bleeding/spotting day
    44
        at least 1 bleeding day (excluding spotting)
    36
        at least 1 bleeding/spotting or SOE
    44
        at least 1 bleeding/SE (excluding SOE)
    44
    Notes
    [12] - FAS with evaluable subjects for this outcome
    No statistical analyses for this end point

    Secondary: Bleeding Patterns in Days by 90-day Reference Periods - Reference Period 3

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    End point title
    		 Bleeding Patterns in Days by 90-day Reference Periods - Reference Period 3
    End point description
    The occurrence of vaginal bleeding was to be recorded by study subjects every day in an e-diary. Bleeding intensity was categorized as: no vaginal bleeding, spotting (less than associated with normal menstruation relative to the subject’s experience with no need for sanitary protection except for panty liners), light (less than associated with normal menstruation relative to the subject’s experience with need for sanitary protection), normal (similar to normal menstruation relative to the subject’s experience) and heavy (more than normal menstruation relative to the subject’s experience). For Bleeding/spotting-free interval at least 2 days without bleeding/spotting preceded and followed by at least 1 bleeding/spotting day. For Spotting-only episode day(s) with spotting preceded and followed by at least 2 bleeding-free days and for Bleeding/spotting episode Day(s) with bleeding/spotting preceded and followed by at least 2 bleeding-free days.
    End point type
    Secondary
    End point timeframe
    At reference period 3 (1 reference period=90-days) during 1-year treatment phase
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    33 [13]
    Units: subjects
        at least 1 bleeding/spotting day
    32
        at least 1 bleeding day (excluding spotting)
    28
        at least 1 bleeding/spotting or SOE
    32
        at least 1 bleeding/SE (excluding SOE)
    32
    Notes
    [13] - FAS with evaluable subjects for this outcome
    No statistical analyses for this end point

    Secondary: Bleeding Patterns in Days by 90-day Reference Periods - Reference Period 4

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    End point title
    		 Bleeding Patterns in Days by 90-day Reference Periods - Reference Period 4
    End point description
    The occurrence of vaginal bleeding was to be recorded by study subjects every day in an e-diary. Bleeding intensity was categorized as: no vaginal bleeding, spotting (less than associated with normal menstruation relative to the subject’s experience with no need for sanitary protection except for panty liners), light (less than associated with normal menstruation relative to the subject’s experience with need for sanitary protection), normal (similar to normal menstruation relative to the subject’s experience) and heavy (more than normal menstruation relative to the subject’s experience). For Bleeding/spotting-free interval at least 2 days without bleeding/spotting preceded and followed by at least 1 bleeding/spotting day. For Spotting-only episode day(s) with spotting preceded and followed by at least 2 bleeding-free days and for Bleeding/spotting episode Day(s) with bleeding/spotting preceded and followed by at least 2 bleeding-free days.
    End point type
    Secondary
    End point timeframe
    At reference period 4 (1 reference period=90-days) during 1-year treatment phase
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    19 [14]
    Units: subjects
        at least 1 bleeding/spotting day
    18
        at least 1 bleeding day (excluding spotting)
    16
        at least 1 bleeding/spotting or SOE
    18
        at least 1 bleeding/SE (excluding SOE)
    18
    Notes
    [14] - FAS with evaluable subjects for this outcome
    No statistical analyses for this end point

    Secondary: Serum Concentration of Total Levonorgestrel

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    End point title
    		 Serum Concentration of Total Levonorgestrel
    End point description
    Geometric mean and percentage geometric coefficient of variation (%CV) were reported. In the table below, "n" signifies the number of subjects evaluable at the corresponding time points.
    End point type
    Secondary
    End point timeframe
    1, 3, 6, 9, 12 months after insertion
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    304 [15]
    Units: nanogram/liter (ng/L)
    geometric mean (geometric coefficient of variation)
        1 month (n=268)
    145 ( 24.7 )
        3 months (n=263)
    110 ( 25.2 )
        6 months (n=258)
    90.9 ( 25.3 )
        9 months (n=246)
    82.9 ( 25.2 )
        12 months (n=220)
    77.8 ( 24.3 )
    Notes
    [15] - FAS
    No statistical analyses for this end point

    Secondary: Serum Concentration of Unbound Levonorgestrel

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    End point title
    		 Serum Concentration of Unbound Levonorgestrel
    End point description
    Geometric mean and (%CV) were reported. In the table below, "n" signifies the number of subjects evaluable at the corresponding time points.
    End point type
    Secondary
    End point timeframe
    1, 3, 6, 9, 12 months after insertion
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    304 [16]
    Units: nanogram/Liter (ng/L)
    geometric mean (geometric coefficient of variation)
        1 month (n=268)
    2.21 ( 20.3 )
        3 months (n=263)
    1.66 ( 20.2 )
        6 months (n=258)
    1.36 ( 20.1 )
        9 months (n=246)
    1.24 ( 20.1 )
        12 months (n=220)
    1.16 ( 19.5 )
    Notes
    [16] - FAS
    No statistical analyses for this end point

    Secondary: Serum Concentration of Sex Hormone Binding Globulin (SHBG)

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    End point title
    		 Serum Concentration of Sex Hormone Binding Globulin (SHBG)
    End point description
    The PK of LNG is dependent on SHBG levels as LNG binds specifically to SHBG with high affinity and SHBG synthesis, in turn, is inhibited by LNG.
    End point type
    Secondary
    End point timeframe
    1, 3, 6, 9, 12 months after insertion
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    0 [17]
    Units: nanomole per liter (nmol/L)
        geometric mean (geometric coefficient of variation)
    ( )
    Notes
    [17] - SHBG needed for calculation of unbound LNG concentration, so data were not summarized and evaluated.
    No statistical analyses for this end point

    Secondary: Investigator's Evaluation of Intrauterine System (IUS) Insertion Procedure

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    End point title
    		 Investigator's Evaluation of Intrauterine System (IUS) Insertion Procedure
    End point description
    The ease of IUS insertion was evaluated by the investigator as easy, slightly difficult, or very difficult.
    End point type
    Secondary
    End point timeframe
    Month 0
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    303 [18]
    Units: subjects
        easy
    286
        slightly difficult
    14
        very difficult
    3
    Notes
    [18] - FAS with evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: Subjects’ Evaluation of Pain During Intrauterine System (IUS) Insertion Procedure

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    End point title
    		 Subjects’ Evaluation of Pain During Intrauterine System (IUS) Insertion Procedure
    End point description
    The subject assessed the pain experienced during the insertion as none, mild, moderate or severe and this was recorded by the investigator.
    End point type
    Secondary
    End point timeframe
    Month 0
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    303 [19]
    Units: subjects
        none
    62
        mild
    104
        moderate
    104
        severe
    33
    Notes
    [19] - FAS with evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: Investigator's Evaluation of Intrauterine System (IUS) Removal Procedure During Treatment Phase

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    End point title
    		 Investigator's Evaluation of Intrauterine System (IUS) Removal Procedure During Treatment Phase
    End point description
    The ease of IUS removal was assessed by investigator as easy, slightly difficult or very difficult.
    End point type
    Secondary
    End point timeframe
    From start of study treatment until 12 months
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    69 [20]
    Units: subjects
        Missing
    4
        Easy
    64
        Slightly difficult
    1
        Very difficult
    0
    Notes
    [20] - FAS with evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: Subject's Evaluation of Pain During Intrauterine System (IUS) Removal Procedure During Treatment Phase

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    End point title
    		 Subject's Evaluation of Pain During Intrauterine System (IUS) Removal Procedure During Treatment Phase
    End point description
    The subject assessed the pain experienced during the removal as none, mild, moderate or severe and this was recorded by the investigator.
    End point type
    Secondary
    End point timeframe
    From start of treatment up to 12 months
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    69 [21]
    Units: subjects
        Missing
    2
        None
    34
        Mild
    25
        Moderate
    8
    Notes
    [21] - FAS with evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: Investigator's Evaluation of Intrauterine System (IUS) Removal Procedure During Overall Study

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    End point title
    		 Investigator's Evaluation of Intrauterine System (IUS) Removal Procedure During Overall Study
    End point description
    The ease of IUS removal was assessed by investigator as easy, slightly difficult or very difficult.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to 36 months (end of optional extension phase)
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    285 [22]
    Units: Subjects
        Easy
    277
        Slightly difficult
    8
        Very difficult
    0
    Notes
    [22] - FAS with evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: Subject's Evaluation of Pain During Intrauterine System (IUS) Removal Procedure During Overall Study

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    End point title
    		 Subject's Evaluation of Pain During Intrauterine System (IUS) Removal Procedure During Overall Study
    End point description
    The subject assessed the pain experienced during the removal as none, mild, moderate or severe and this was recorded by the investigator.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to 36 months (end of extension phase)
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    287 [23]
    Units: subjects
        None
    134
        Mild
    116
        Moderate
    34
        Severe
    3
    Notes
    [23] - FAS with evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: Discontinuation Rates by Reason and Year

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    End point title
    		 Discontinuation Rates by Reason and Year
    End point description
    The discontinuation rate was calculated from the number of subjects with an expulsion, plus those who had LCS12 removed due to partial expulsion or perforation, plus those who discontinued study treatment for other reasons. The discontinuation rate was classified yearly (Year [Y] 1, Y2 and Y3) for below reasons - Any reason, any adverse event, LCS expulsion, bleeding pattern alterations, increased female genital bleeding, decreased female genital bleeding, and unspecified (unspe) or irregular (irr.) female genital bleeding. In the table below, "n" signifies the number of subjects evaluable at the corresponding time points.
    End point type
    Secondary
    End point timeframe
    From the start of study treatment until the end of extension phase up to 3 years
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    304 [24]
    Units: Percentage of subjects
    number (not applicable)
        Y1, Any reason (n=304)
    15.8
        Y1, Any adverse event (n=304)
    13.2
        Y1, LCS expulsion (n=304)
    3.3
        Y1, Bleeding pattern alterations (n=304)
    3
        Y1, Increased female genital bleeing (n=304)
    2.3
        Y1, Decreased female genital bleeding (n=304)
    0
        Y1, Unspe./irr. female genital bleeding (n=304)
    2
        Y2, Any reason (n=234)
    7.7
        Y2, Any adverse event (n=234)
    3.8
        Y2, LCS expulsion (n=234)
    1.3
        Y2, Bleeding pattern alterations (n=234)
    0.4
        Y2, Increased female genital bleeding (n=234)
    0.4
        Y2, Decreased female genital bleeding (n=234)
    0
        Y2, Unspe./irr. female genital bleeding (n=234)
    0
        Y3, Any reason (n=205)
    16.1
        Y3, Any adverse event (n=205)
    7.8
        Y3, LCS expulsion (n=205)
    1
        Y3, Bleeding pattern alterations (n=205)
    4.4
        Y3, Increased female genital bleeding (n=205)
    4.4
        Y3, Decreased female genital bleeding (n=205)
    0
        Y3, Unspe./irr. femal genital bleeding (n=205)
    0
    Notes
    [24] - FAS
    No statistical analyses for this end point

    Secondary: Discontinuation Rates by Reason

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    End point title
    		 Discontinuation Rates by Reason
    End point description
    Discontinuation rate was the number and percentage of subjects who discontinued the study drug during the overall period (includes both treatment phase and extension period).
    End point type
    Secondary
    End point timeframe
    Up to 36 months
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    304 [25]
    Units: Percentage of subjects
    number (not applicable)
        Any reason
    32.6
        Any adverse event
    21.4
        LCS expulsion
    4.9
        Bleeding pattern alterations
    6.3
        Increased female genital bleeding
    5.6
        Decreased female genital bleeding
    0
        Unspecified or irregular female genital bleeding
    0.7
    Notes
    [25] - FAS
    No statistical analyses for this end point

    Secondary: Discontinuation Rates by Reason and Parity During 1 Year Treatment Phase

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    End point title
    		 Discontinuation Rates by Reason and Parity During 1 Year Treatment Phase
    End point description
    Discontinuation rate by reason and parity was the number and percentage of subjects who discontinued the study drug during the 1 year treatment phase.
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 Levonorgestrel (BAY86-5028)
    Number of subjects analysed
    297 [26]
    Units: Percentage of subjects
    number (not applicable)
        Nulliparous (NP): Any reason
    16.8
        NP: LCS12 expulsion
    3.4
        NP: Bleeding pattern alterations
    3
        NP: Any adverse event
    13.5
        Parous (P): Any reason
    14.3
        P: LCS12 expulsion
    0
        P: Bleeding pattern alterations
    0
        P: Any adverse event
    0
    Notes
    [26] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study treatment until the extension phase for up to 3 years
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Levonorgestrel (BAY86-5028)
    Reporting group description
    		 Subjects received levonorgestrel (LNG) intrauterine contraceptive system with an initial in vitro release rate of 12 microgram LNG/day (LCS12) for up to 3 years (the extension phase after 12 months was optional).

    Serious adverse events
    		 Levonorgestrel (BAY86-5028)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    34 / 304 (11.18%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Wisdom teeth removal
         subjects affected / exposed
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Allergy prophylaxis
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mammoplasty
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Benign intracranial hypertension
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion early
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Breast enlargement
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic pain
         subjects affected / exposed
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Adnexal torsion
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Drug dependence
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute psychosis
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Endometritis
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Scarlet fever
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    5 / 304 (1.64%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abscess jaw
         subjects affected / exposed
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Levonorgestrel (BAY86-5028)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    257 / 304 (84.54%)
    Investigations
    Chlamydia test positive
         subjects affected / exposed
    10 / 304 (3.29%)
         occurrences all number
    11
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    41 / 304 (13.49%)
         occurrences all number
    42
    Surgical and medical procedures
    Wisdom teeth removal
         subjects affected / exposed
    9 / 304 (2.96%)
         occurrences all number
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    40 / 304 (13.16%)
         occurrences all number
    59
    Migraine
         subjects affected / exposed
    7 / 304 (2.30%)
         occurrences all number
    8
    General disorders and administration site conditions
    Device expulsion
         subjects affected / exposed
    15 / 304 (4.93%)
         occurrences all number
    15
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    7 / 304 (2.30%)
         occurrences all number
    9
    Abdominal pain
         subjects affected / exposed
    30 / 304 (9.87%)
         occurrences all number
    36
    Diarrhoea
         subjects affected / exposed
    8 / 304 (2.63%)
         occurrences all number
    8
    Abdominal pain upper
         subjects affected / exposed
    8 / 304 (2.63%)
         occurrences all number
    15
    Nausea
         subjects affected / exposed
    15 / 304 (4.93%)
         occurrences all number
    16
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    9 / 304 (2.96%)
         occurrences all number
    9
    Cervical dysplasia
         subjects affected / exposed
    7 / 304 (2.30%)
         occurrences all number
    9
    Dysmenorrhoea
         subjects affected / exposed
    85 / 304 (27.96%)
         occurrences all number
    111
    Menorrhagia
         subjects affected / exposed
    8 / 304 (2.63%)
         occurrences all number
    8
    Ovarian cyst
         subjects affected / exposed
    26 / 304 (8.55%)
         occurrences all number
    32
    Pelvic pain
         subjects affected / exposed
    63 / 304 (20.72%)
         occurrences all number
    83
    Vaginal discharge
         subjects affected / exposed
    7 / 304 (2.30%)
         occurrences all number
    7
    Vaginal haemorrhage
         subjects affected / exposed
    19 / 304 (6.25%)
         occurrences all number
    24
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 304 (2.30%)
         occurrences all number
    7
    Oropharyngeal pain
         subjects affected / exposed
    13 / 304 (4.28%)
         occurrences all number
    13
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    32 / 304 (10.53%)
         occurrences all number
    35
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    12 / 304 (3.95%)
         occurrences all number
    12
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    9 / 304 (2.96%)
         occurrences all number
    12
    Bacterial vaginosis
         subjects affected / exposed
    7 / 304 (2.30%)
         occurrences all number
    9
    Bronchitis
         subjects affected / exposed
    13 / 304 (4.28%)
         occurrences all number
    14
    Gastroenteritis
         subjects affected / exposed
    14 / 304 (4.61%)
         occurrences all number
    17
    Cystitis
         subjects affected / exposed
    30 / 304 (9.87%)
         occurrences all number
    39
    Gastroenteritis viral
         subjects affected / exposed
    8 / 304 (2.63%)
         occurrences all number
    8
    Influenza
         subjects affected / exposed
    24 / 304 (7.89%)
         occurrences all number
    31
    Sinusitis
         subjects affected / exposed
    12 / 304 (3.95%)
         occurrences all number
    20
    Urinary tract infection
         subjects affected / exposed
    20 / 304 (6.58%)
         occurrences all number
    31
    Nasopharyngitis
         subjects affected / exposed
    46 / 304 (15.13%)
         occurrences all number
    64
    Vaginal infection
         subjects affected / exposed
    19 / 304 (6.25%)
         occurrences all number
    25
    Vulvovaginal candidiasis
         subjects affected / exposed
    18 / 304 (5.92%)
         occurrences all number
    21
    Vulvovaginal mycotic infection
         subjects affected / exposed
    8 / 304 (2.63%)
         occurrences all number
    12
    Chlamydial infection
         subjects affected / exposed
    12 / 304 (3.95%)
         occurrences all number
    13
    Vaginitis chlamydial
         subjects affected / exposed
    10 / 304 (3.29%)
         occurrences all number
    12

    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.
    Occurrence of "±” in relation with geometric CV is autogenerated. Decimal places were automatically truncated if last decimal equals zero. SHBG needed for calculation of unbound LNG concentration, so data were not summarized and evaluated.
    For support, Contact us.
    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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