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    Clinical Trial Results:
    Multicenter, open-label, randomized, controlled parallel-group study to assess discontinuation rates, bleeding patterns, user satisfaction and adverse event profile of LCS12 in comparison to etonogestrel subdermal implant over 12 months of use in women 18 to 35 years of age

    Summary
    EudraCT number
    		 2010-023911-32
    Trial protocol
    		 SE   FI   GB   NO  
    Global end of trial date
    30 Apr 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    08 Sep 2016
    First version publication date
    12 May 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
    BAY86-5028/13363
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01397097
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, D-51368, 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)
    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
    30 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate that discontinuation rates in women (ages 18-35 years inclusive) using Levonorgestrel intrauterine delivery system with 12 microgram levonorgestrel per day initial in vitro release rate (LCS12) were not higher than those seen in women using Etonogestrel (ENG) subdermal implant over a period of 12 months. The objective of the 2‑year extension phase was to evaluate safety 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 representative. Participating subjects 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
    15 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
    Norway: 148
    Country: Number of subjects enrolled
    Sweden: 124
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    Finland: 362
    Country: Number of subjects enrolled
    France: 67
    Country: Number of subjects enrolled
    Australia: 40
    Worldwide total number of subjects
    766
    EEA total number of subjects
    726
    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)
    766
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 38 study centers in 6 countries Sweden, Finland, France, United Kingdom, Norway, and Australia, between 15 September 2011 (first subject first visit) and 30 April 2015 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall 952 subjects were screened, of them 766 enrolled and randomized to treatment LCS12 group (385) or ENG implant group (381) in 1-year comparative treatment phase. Of the 382 subjects assigned to LCS12 treatment in the first year, 283 subjects entered the optional 2-year extension phase.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 LCS12 (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 (LNG)
    Investigational medicinal product code
    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.

    Arm title
    		 Etonogestrel (ENG)
    Arm description
    		 Subjects received 68 mg etonorgestrel implant for subdermal use at initial release rate 60 – 70 mcg/day for 12 months with an optional extension phase for further 24 months under standard care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etonogestrel (ENG)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Implant
    Routes of administration
    Subdermal use
    Dosage and administration details
    Subjects received 68 mg etonorgestrel implant for subdermal use at initial release rate 60 – 70 mcg/day for 12 months with an optional extension phase for further 24 months under standard care.

    Number of subjects in period 1
    		LCS12 (BAY86-5028) Etonogestrel (ENG)
    Started
    385
    381
    Treated
    381
    381
    Completed
    304
    279
    Not completed
    81
    102
         Insertion failure
    4
    -
         Consent withdrawn by subject
    5
    4
         Protocol violation
    1
    -
         Wish for pregnancy
    3
    4
         Death
    1
    -
         Other
    -
    1
         Pregnancy
    3
    -
         Adverse event
    54
    83
         Lost to follow-up
    10
    10
    Period 2
    Period 2 title
    Extension phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 LCS12 (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 (LNG)
    Investigational medicinal product code
    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
    		LCS12 (BAY86-5028)
    Started
    283
    Completed
    199
    Not completed
    84
         Consent withdrawn by subject
    10
         Wish for pregnancy
    18
         Other
    9
         Pregnancy
    1
         Adverse event
    41
         Lost to follow-up
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LCS12 (BAY86-5028)
    Reporting group description
    		 Subjects received LCS12 for 12 months with an optional extension phase for further 24 months.

    Reporting group title
    Etonogestrel (ENG)
    Reporting group description
    		 Subjects received 68 mg etonorgestrel implant for subdermal use at initial release rate 60 – 70 mcg/day for 12 months with an optional extension phase for further 24 months under standard care.

    Reporting group values
    		 LCS12 (BAY86-5028) Etonogestrel (ENG) Total
    Number of subjects
    		 385 381 766
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 385 381 766
    Gender categorical
    Units: Subjects
        Female
    		 385 381 766

    End points

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    End points reporting groups
    Reporting group title
    LCS12 (BAY86-5028)
    Reporting group description
    		 Subjects received LCS12 for 12 months with an optional extension phase for further 24 months.

    Reporting group title
    Etonogestrel (ENG)
    Reporting group description
    		 Subjects received 68 mg etonorgestrel implant for subdermal use at initial release rate 60 – 70 mcg/day for 12 months with an optional extension phase for further 24 months under standard care.
    Reporting group title
    LCS12 (BAY86-5028)
    Reporting group description
    		 Subjects received LCS12 for 12 months with an optional extension phase for further 24 months.

    Subject analysis set title
    Safety analysis set (SAF) Treatment Phase
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF included all subjects who had successful or unsuccessful attempt of LCS12 or ENG sub-dermal implant insertion.

    Subject analysis set title
    Safety analysis set (SAF) - Overall Study
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF included subjects who attempted at least one successful or unsuccessful insertion of LCS12 during the overall study.

    Subject analysis set title
    Full analysis set (FAS)-Treatment Phase
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS included all randomized subjects who received treatment (had a successful LCS12/ENG sub-dermal implant insertion).

    Subject analysis set title
    Full analysis set (FAS) - Overall Study
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS included all randomized subjects who received treatment (i.e., had a successful LCS12 insertion) during overall study.

    Subject analysis set title
    LCS12
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received LCS12 for 36 months.

    Subject analysis set title
    ENG – Treatment Phase
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 68 mg ENG implant for subdermal use at initial release rate 60 – 70 mcg/day for 12 months.

    Subject analysis set title
    LCS12 – Treatment phase 1 Year
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received LCS12 for until end of first year of treatment.

    Subject analysis set title
    LCS12 – Treatment phase 2 Year
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received LCS12 from start of 2nd year until end of 2nd year.

    Subject analysis set title
    LCS12 – Treatment phase 3 Year
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received LCS12 from start of 3rd year until end of 3rd year.

    Primary: Discontinuation Rate at 12 Month

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    End point title
    		 Discontinuation Rate at 12 Month [1]
    End point description
    Discontinuation rate was the number and percentage of subjects who discontinued the study drug during the 12-month comparative treatment phase.
    End point type
    Primary
    End point timeframe
    Month 12
    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
    		 LCS12 (BAY86-5028) Etonogestrel (ENG)
    Number of subjects analysed
    378 [2]
    381 [3]
    Units: Percentage of subjects
        number (not applicable)
    19.58
    26.77
    Notes
    [2] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    [3] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: Discontinuation Rates for any Reason and for Specific Reasons - Treatment Phase

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    End point title
    		 Discontinuation Rates for any Reason and for Specific Reasons - Treatment Phase
    End point description
    Discontinuation rate was the number and percentage of subjects who discontinued the study drug during the treatment phase. The reasons of discontinuation were recorded and analysed over a period.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 LCS12 (BAY86-5028) Etonogestrel (ENG)
    Number of subjects analysed
    378 [4]
    381 [5]
    Units: Percentage of subjects
    number (not applicable)
        Any reason
    19.6
    26.8
        Wish for pregnancy
    0.8
    1
        Any reason except-wish for pregnancy
    18.8
    25.7
        LCS12 expulsion
    0.8
    0
        Perforations (LCS12 group)
    0
    0
        Adverse events
    14.3
    21.8
        ENG subdermal implant site infection or expulsion
    0
    0
        Deeply inserted ENG subdermal implant
    0
    0
        Female genital bleeding pattern alterations
    4.2
    11.5
    Notes
    [4] - FAS (Treatment Phase) with evaluable subjects for this outcome measure.
    [5] - FAS (Treatment Phase)
    No statistical analyses for this end point

    Secondary: Overall Discontinuation Rate by Kaplan-Meier Analysis – Treatment Phase

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    End point title
    		 Overall Discontinuation Rate by Kaplan-Meier Analysis – Treatment Phase
    End point description
    Overall discontinuation rates were analyzed by Kaplan-Meier analyses and presented as half yearly drop-out rates.
    End point type
    Secondary
    End point timeframe
    At first half year, second half year and third half year
    End point values
    		 LCS12 (BAY86-5028) Etonogestrel (ENG)
    Number of subjects analysed
    378 [6]
    381 [7]
    Units: Percentage of subjects
    number (not applicable)
        First half year
    9.52
    14.7
        Second half year
    10.82
    14.15
        Third half year
    0.47
    0
    Notes
    [6] - FAS (Treatment phase) with evaluable subjects for this outcome measure.
    [7] - FAS (Treatment phase)
    No statistical analyses for this end point

    Secondary: Discontinuation Rates by Reason During Overall Phase

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    End point title
    		 Discontinuation Rates by Reason During Overall Phase
    End point description
    Discontinuation rate was the number and percentage of subjects who discontinued the study drug during the overall phase. The reasons of discontinuation were recorded and analysed over a period.
    End point type
    Secondary
    End point timeframe
    From start of treatment until 36 months
    End point values
    		 LCS12
    Number of subjects analysed
    378 [8]
    Units: Percentage of subjects
    number (not applicable)
        Any reason
    41.8
        Wish for pregnancy
    5.6
        Any reason except-wish for pregnancy
    36.2
        Pregnancy
    1.1
        Adverse events
    25.1
        LCS12 expulsion
    1.3
        Perforations
    0
        Female genital bleeding pattern alterations
    8.5
    Notes
    [8] - FAS (Overall study) with evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: Discontinuation Rates by Reason and Parity During Overall Phase

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    End point title
    		 Discontinuation Rates by Reason and Parity During Overall Phase
    End point description
    Discontinuation rate was the number and percentage of subjects who discontinued the study drug during the overall phase. The reasons of discontinuation were recorded and analysed over a period. Parity determined as nulliparous if the number of birth is 0 and parous if the number of birth is 1, 2, 3…n, including vaginal delivery and Cesarean section. The reasons of discontinuation were recorded and analysed over a period in nulliparous and parous.
    End point type
    Secondary
    End point timeframe
    From start of treatment until month 36
    End point values
    		 LCS12
    Number of subjects analysed
    378 [9]
    Units: Percentage of subjects
    number (not applicable)
        Nulliparous: Any reason (n=290)
    43.1
        Nulliparous: Wish for pregnancy (n=290)
    5.5
        Nulliparous: Except-wish for pregnancy (n=290)
    37.6
        Nulliparous: Pregnancy (n=290)
    0.7
        Nulliparous: LCS12 expulsion (n=290)
    1.4
        Nulliparous: Perforations (n=290)
    0
        Nulliparous: Adverse events (n=290)
    26.6
        Parous: Any reason (n=88)
    37.5
        Parous: Wish for pregnancy (n=88)
    5.7
        Parous: Except-wish for pregnancy (n=88)
    31.8
        Parous: Pregnancy (n=88)
    2.3
        Parous: LCS12 expulsion (n=88)
    1.1
        Parous: Perforations (n=88)
    0
        Parous: Adverse events (n=88)
    20.5
    Notes
    [9] - FAS (Overall study) with evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: Discontinuation Rates by Reason and Year During Overall Phase

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    End point title
    		 Discontinuation Rates by Reason and Year During Overall Phase
    End point description
    Discontinuation rate was the number and percentage of subjects who discontinued the study drug during the overall phase. The reasons of discontinuation were recorded and analysed over a period.
    End point type
    Secondary
    End point timeframe
    From start of treatment until month 36
    End point values
    		 LCS12 – Treatment phase 1 Year LCS12 – Treatment phase 2 Year LCS12 – Treatment phase 3 Year
    Number of subjects analysed
    378 [10]
    294 [11]
    233 [12]
    Units: Percentage of subjects
    number (not applicable)
        Any reason
    19
    17.7
    14.6
        Wish for pregnancy
    0.8
    3.1
    3.9
        Any reason except-wish for pregnancy
    18.3
    14.6
    10.7
        Pregnancy
    0.5
    0.3
    0.4
        Adverse events
    14.3
    9.2
    6
        LCS12 expulsion
    0.8
    0.7
    0
        Perforations
    0
    0
    0
        Female genital bleeding pattern alterations
    4.2
    3.4
    2.6
    Notes
    [10] - FAS (Overall study) with evaluable subjects of the respective treatment year for this measure.
    [11] - FAS (Overall study) with evaluable subjects of the respective treatment year for this measure.
    [12] - FAS (Overall study) with evaluable subjects of the respective treatment year for this measure.
    No statistical analyses for this end point

    Secondary: Overall Satisfaction Rate in Year 1

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    End point title
    		 Overall Satisfaction Rate in Year 1
    End point description
    Satisfaction was to be 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? 1. Very satisfied 2. Satisfied 3. Neither satisfied nor dissatisfied 4. Dissatisfied 5. Very dissatisfied. The overall satisfaction rate is the percentage of subjects selecting “1. Very satisfied” or “2. Satisfied” for the above question. Here, in the below table, number of subjects (n) signifies evaluable subjects for the respective category.
    End point type
    Secondary
    End point timeframe
    At 6 and 12 months
    End point values
    		 LCS12 (BAY86-5028) Etonogestrel (ENG)
    Number of subjects analysed
    365 [13]
    369 [14]
    Units: Percentage of subjects
    number (not applicable)
        Month 6 (M6): Very satisfied (n=365,369)
    44.1
    46.9
        M6: Satisfied (n=365,369)
    38.6
    24.4
        M6: Neither satisfied nor dissatisfied (n=365,369)
    9
    14.4
        M6: Dissatisfied (n=365,369)
    6.8
    9.8
        M6: Very dissatisfied (n=365,369)
    1.4
    4.6
        Month 12 (M12): Very satisfied (n=327,319)
    53.8
    49.5
        M12: Satisfied (n=327,319)
    32.7
    26.3
        M12: Neither satisfied nor dissatisfied(n=327,319)
    6.7
    10.3
        M12: Dissatisfied (n=327,319)
    5.8
    11.9
        M12: Very dissatisfied (n=327,319)
    0.9
    1.9
    Notes
    [13] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    [14] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: User Satisfaction – Acceptability of the Administration of Study Treatment

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    End point title
    		 User Satisfaction – Acceptability of the Administration of Study Treatment
    End point description
    The degree of user satisfaction was assessed at the end-of-study visit using an eight item questionnaire. One of the items assessed was acceptability of study treatment which was categorized into the following: acceptable without inconvenience/discomfort (I/D), acceptable with some I/D, not acceptable with moderate I/D, and not acceptable with extreme I/D. Here, in the below table, number of subjects (n) signifies evaluable subjects for the respective category. Here, in the below table, number of subjects (n) signifies evaluable subjects for the respective category.
    End point type
    Secondary
    End point timeframe
    month 6 and 12
    End point values
    		 LCS12 (BAY86-5028) Etonogestrel (ENG)
    Number of subjects analysed
    358 [15]
    366 [16]
    Units: Subject
        M6: Acceptable without I/D (n=331, 318)
    81
    201
        M6: Acceptable with some I/D (n=331, 318)
    203
    109
        M6: Not acceptable with moderate I/D (n=331, 318)
    16
    3
        M6: Not acceptable with extreme I/D (n=331, 318)
    31
    5
        M12: Acceptable without I/D (n=357, 366)
    93
    210
        M12: Acceptable with some I/D (n=357, 366)
    204
    136
        M12: Not acceptable with moderate I/D (n=357, 366)
    27
    14
        M12: Not acceptable with extreme I/D (n=357, 366)
    33
    6
    Notes
    [15] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    [16] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: User Satisfaction – Choices Upon Completion of the Study

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    End point title
    		 User Satisfaction – Choices Upon Completion of the Study
    End point description
    At visit month 6 and month 12 the choices upon completion of the study has been asked from the subjects using six item questionnaire. Questionnaires for the continuation of the study treatment was categorized into the following: continue with study treatment, use a different hormonal contraceptive, discontinue use of all contraceptives, continue with study treatment, and use different hormonal contraceptives. Here, in the below table, number of subjects (n) signifies evaluable subjects for the respective category.
    End point type
    Secondary
    End point timeframe
    Month 6 and 12
    End point values
    		 LCS12 (BAY86-5028) Etonogestrel (ENG)
    Number of subjects analysed
    357 [17]
    366 [18]
    Units: Subject
        M6 m: Continue with study treatment (n=329, 317)
    252
    236
        M6: Different hormonal Contraceptive (n=329, 317)
    18
    13
        M6: Different Contraceptive method (n=329, 317)
    8
    15
        M6: Discontinue of all Contraceptive (n=329, 317)
    0
    3
        M6: Undecided (n=329, 317)
    51
    50
        M12: Continue with study treatment (n=357, 366)
    251
    214
        M12: Different hormonal Contraceptive (n=357, 366)
    34
    58
        M12: Different Contraceptive method (n=357, 366)
    30
    56
        M12: Discontinue of all Contraceptive (n=357, 366)
    5
    5
        M12: No need Contraceptive this time (n=357, 366)
    8
    12
        M12: Undecided (n=357, 366)
    29
    21
    Notes
    [17] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    [18] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: User Satisfaction – Amount of Menstrual Bleeding

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    End point title
    		 User Satisfaction – Amount of Menstrual Bleeding
    End point description
    The degree of user satisfaction was assessed at the end-of-study visit using an eight item questionnaire. One of the items assessed was acceptability of study treatment which was categorized into the following: acceptable without inconvenience/discomfort (I/D), acceptable with some I/D, not acceptable with moderate I/D, and not acceptable with extreme I/D. Here, in the below table, number of subjects (n) signifies evaluable subjects for the respective category.
    End point type
    Secondary
    End point timeframe
    Month 6 and 12
    End point values
    		 LCS12 (BAY86-5028) Etonogestrel (ENG)
    Number of subjects analysed
    357 [19]
    365 [20]
    Units: Subject
        M6: Decreased (n= 331, 317)
    254
    201
        M6: Not Changed (n= 331, 317)
    61
    73
        M6: Increased (n= 331, 317)
    16
    43
        M12: Decreased (n= 357, 365)
    203
    147
        M12: Not Changed (n= 357, 365)
    121
    142
        M12: Increased (n= 357, 365)
    33
    76
    Notes
    [19] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    [20] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: User Satisfaction – Satisfaction With Menstrual Bleeding Pattern

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    End point title
    		 User Satisfaction – Satisfaction With Menstrual Bleeding Pattern
    End point description
    The degree of user satisfaction with menstrual bleeding absence was assessed at the end-of-study visit using four item questionnaire. Questionnaires for this assessment were categorized into very satisfied, somewhat satisfied, neither satisfied nor dissatisfied, dissatisfied, very dissatisfied and not applicable. Here, in the below table, number of subjects (n) signifies evaluable subjects for the respective category.
    End point type
    Secondary
    End point timeframe
    Month 6 and 12
    End point values
    		 LCS12 (BAY86-5028) Etonogestrel (ENG)
    Number of subjects analysed
    358 [21]
    366 [22]
    Units: Subjects
        M6: Very satisfied (n=331, 318)
    87
    66
        M6: Somewhat satisfied (n=331, 318)
    123
    66
        M6: Neither satisfied nor dissatisfied (n=331,318)
    64
    54
        M6: Dissatisfied (n=331, 318)
    30
    55
        M6: Very dissatisfied (n=331, 318)
    9
    23
        M6: Not applicable (n=331, 318)
    18
    54
        M12: Very satisfied (n=358, 366)
    119
    75
        M12: Somewhat satisfied (n=358, 366)
    99
    48
        M12: Neither satisfied nor dissatisfied(n=358,366)
    69
    68
        M12: Dissatisfied (n=358, 366)
    35
    67
        M12: Very dissatisfied (n=358, 366)
    21
    50
        M12: Not applicable (n=358, 366)
    15
    58
    Notes
    [21] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    [22] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: User Satisfaction – Frequency of Experiencing Unexpected Bleeding

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    End point title
    		 User Satisfaction – Frequency of Experiencing Unexpected Bleeding
    End point description
    The degree of user satisfaction with menstrual bleeding absence was assessed at the end-of-study visit using four item questionnaire. Questionnaires for this assessment were categorized into never, seldom, often and very often. Here, in the below table, number of subjects (n) signifies evaluable subjects for the respective category.
    End point type
    Secondary
    End point timeframe
    Month 6 and 12
    End point values
    		 LCS12 (BAY86-5028) Etonogestrel (ENG)
    Number of subjects analysed
    358 [23]
    366 [24]
    Units: Subjects
        M6: Never (n=331, 317)
    111
    111
        M6: Seldom (n=331, 317)
    170
    110
        M6: Often (n=331, 317)
    40
    67
        M6: Very often (n=331, 317)
    10
    29
        M12: Never (n=358, 366)
    158
    119
        M12: Seldom (n=358, 366)
    150
    116
        M12: Often (n=358, 366)
    34
    81
        M12: Very often (n=358, 366)
    16
    50
    Notes
    [23] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    [24] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: User Satisfaction – Satisfaction With Menstrual Bleeding Absence

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    End point title
    		 User Satisfaction – Satisfaction With Menstrual Bleeding Absence
    End point description
    The degree of user satisfaction with menstrual bleeding absence was assessed at the end-of-study visit using four item questionnaire. Questionnaires for this assessment were categorized into very satisfied, somewhat satisfied, neither satisfied nor dissatisfied and dissatisfied. Here, in the below table, number of subjects (n) signifies evaluable subjects for the respective category. ‘99999’ in the posting indicates that data were not calculated.
    End point type
    Secondary
    End point timeframe
    Month 6 and 12
    End point values
    		 LCS12 (BAY86-5028) Etonogestrel (ENG)
    Number of subjects analysed
    141 [25]
    193 [26]
    Units: Subjects
        M6: Very satisfied (n=117,189)
    86
    136
        M6: Somewhat satisfied (n=117,189)
    21
    33
        M6: Neither satisfied nor dissatisfied (n=117,189)
    10
    17
        M6: Dissatisfied (n=117,189)
    0
    3
        M12: Very satisfied (n=141,193)
    111
    150
        M12: Somewhat satisfied (n=141,193)
    18
    29
        M12: Neither satisfied nor dissatisfied(n=141,193)
    11
    12
        M12: Dissatisfied (n=141,193)
    0
    2
        M12: Very dissatisfied (n=141,193)
    1
    0
    Notes
    [25] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    [26] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: Contraceptive Efficacy: Pearl Index (PI)- Treatment Phase

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    End point title
    		 Contraceptive Efficacy: Pearl Index (PI)- Treatment Phase
    End point description
    The Pearl Index was defined as the number of pregnancies per 100 woman years (WYs). Given the assumption that the number of pregnancies follows a Poisson distribution, the Pearl Index thus is the mean of this distribution.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 LCS12 (BAY86-5028) Etonogestrel (ENG)
    Number of subjects analysed
    378 [27]
    381 [28]
    Units: pregnancies per 100 women years
        arithmetic mean (confidence interval 95%)
    0.9 (0.19 to 2.63)
    0 (0 to 1.18)
    Notes
    [27] - FAS (Treatment Phase) included evaluable subjects for this outcome measure.
    [28] - FAS (Treatment Phase)
    No statistical analyses for this end point

    Secondary: Contraceptive Efficacy: Pearl Index-Overall Study, first year, Second year, Third year, Up to Second year, Up to Third year and Overall of the treatment

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    End point title
    		 Contraceptive Efficacy: Pearl Index-Overall Study, first year, Second year, Third year, Up to Second year, Up to Third year and Overall of the treatment
    End point description
    The Pearl Index was defined as the number of pregnancies per 100 woman years (WYs). Given the assumption that the number of pregnancies follows a Poisson distribution, the Pearl Index thus is the mean of this distribution. Here, in the below table, number of subjects (n) signifies evaluable subjects for the respective category.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to Month 36
    End point values
    		 LCS12
    Number of subjects analysed
    378 [29]
    Units: Pregnancies per 100 women years
    arithmetic mean (confidence interval 95%)
        Year 1 (n=378)
    0.92 (0.19 to 2.7)
        Year 2 (n=295)
    0.39 (0.01 to 2.15)
        Year 3 (n=237)
    0.98 (0.12 to 3.53)
        2 Years (n=378)
    0.68 (0.19 to 1.75)
        3 Years (n=378)
    0.76 (0.28 to 1.65)
        Overall (n=378)
    0.76 (0.28 to 1.65)
    Notes
    [29] - FAS (overall study) with evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Secondary: LNG Residual Content Analysis

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    End point title
    		 LNG Residual Content Analysis
    End point description
    The residual LNG content was determined in the used LCS12 which was collected from the subjects who prematurely discontinued study treatment in order to determine the performance of LCS12. Subjects who were discontinued from the study between 11 days and 609 days were reported for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Between 11 days and 609 days and after 609 days
    End point values
    		 LCS12
    Number of subjects analysed
    81 [30]
    Units: milligram
    number (not applicable)
        Immediate after insertion
    13.7
        After 609 days
    9.5
    Notes
    [30] - FAS (Overall study) with evaluable subjects for this outcome measure.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment up to Month 12 for the subjects in comparative treatment phase and up to Year 3 for the subjects in extension phase
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    LCS12
    Reporting group description
    		 Subjects received LCS12 for 36 months.

    Reporting group title
    ENG - Treatment Phase
    Reporting group description
    		 Subjects received 68 mg ENG implant for sub-dermal use at initial release rate 60 - 70 microgram per day (mcg/day) for 12 months.

    Reporting group title
    LCS12 - Treatment phase 3 Year
    Reporting group description
    		 Subjects received LCS12 from start of 3rd year until end of 3rd year.

    Reporting group title
    LCS12 - Treatment phase 2 Year
    Reporting group description
    		 Subjects received LCS12 from start of 2nd year until end of 2nd year.

    Reporting group title
    LCS12 - Treatment phase 1 Year
    Reporting group description
    		 Subjects received LCS12 for until end of first year of treatment.

    Serious adverse events
    		 LCS12 ENG - Treatment Phase LCS12 - Treatment phase 3 Year LCS12 - Treatment phase 2 Year LCS12 - Treatment phase 1 Year
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 382 (4.71%)
    9 / 381 (2.36%)
    7 / 234 (2.99%)
    4 / 293 (1.37%)
    8 / 382 (2.09%)
         number of deaths (all causes)
    1
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian adenoma
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    1 / 234 (0.43%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 381 (0.26%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 381 (0.26%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    1 / 234 (0.43%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 381 (0.26%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 381 (0.26%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 381 (0.26%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention postoperative
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    1 / 382 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abdominoplasty
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    1 / 382 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroidectomy
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    1 / 293 (0.34%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 381 (0.26%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ruptured ectopic pregnancy
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    1 / 234 (0.43%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biochemical pregnancy
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    1 / 293 (0.34%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy of unknown location
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    1 / 234 (0.43%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ectopic pregnancy with contraceptive device
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    1 / 382 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Food poisoning
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    1 / 293 (0.34%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 381 (0.26%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    1 / 382 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tracheomalacia
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 381 (0.26%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    1 / 382 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Endocrine disorders
    Basedow's disease
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    1 / 382 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    1 / 382 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prognathism
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    1 / 382 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    2 / 382 (0.52%)
    1 / 381 (0.26%)
    1 / 234 (0.43%)
    0 / 293 (0.00%)
    1 / 382 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    1 / 234 (0.43%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    1 / 293 (0.34%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 381 (0.26%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 381 (0.26%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 381 (0.26%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    1 / 234 (0.43%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 381 (0.00%)
    1 / 234 (0.43%)
    0 / 293 (0.00%)
    0 / 382 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LCS12 ENG - Treatment Phase LCS12 - Treatment phase 3 Year LCS12 - Treatment phase 2 Year LCS12 - Treatment phase 1 Year
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    298 / 382 (78.01%)
    186 / 381 (48.82%)
    55 / 234 (23.50%)
    75 / 293 (25.60%)
    270 / 382 (70.68%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    57 / 382 (14.92%)
    6 / 381 (1.57%)
    6 / 234 (2.56%)
    0 / 293 (0.00%)
    51 / 382 (13.35%)
         occurrences all number
    57
    6
    6
    0
    51
    Nervous system disorders
    Headache
         subjects affected / exposed
    44 / 382 (11.52%)
    42 / 381 (11.02%)
    3 / 234 (1.28%)
    1 / 293 (0.34%)
    41 / 382 (10.73%)
         occurrences all number
    72
    56
    3
    1
    68
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    30 / 382 (7.85%)
    7 / 381 (1.84%)
    1 / 234 (0.43%)
    4 / 293 (1.37%)
    26 / 382 (6.81%)
         occurrences all number
    41
    7
    1
    4
    36
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    64 / 382 (16.75%)
    27 / 381 (7.09%)
    20 / 234 (8.55%)
    32 / 293 (10.92%)
    21 / 382 (5.50%)
         occurrences all number
    80
    27
    23
    34
    23
    Dysmenorrhoea
         subjects affected / exposed
    137 / 382 (35.86%)
    29 / 381 (7.61%)
    4 / 234 (1.71%)
    14 / 293 (4.78%)
    128 / 382 (33.51%)
         occurrences all number
    170
    30
    5
    14
    151
    Uterine spasm
         subjects affected / exposed
    61 / 382 (15.97%)
    0 / 381 (0.00%)
    0 / 234 (0.00%)
    0 / 293 (0.00%)
    61 / 382 (15.97%)
         occurrences all number
    66
    0
    0
    0
    66
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    59 / 382 (15.45%)
    59 / 381 (15.49%)
    4 / 234 (1.71%)
    8 / 293 (2.73%)
    49 / 382 (12.83%)
         occurrences all number
    66
    61
    4
    8
    54
    Infections and infestations
    Influenza
         subjects affected / exposed
    18 / 382 (4.71%)
    24 / 381 (6.30%)
    1 / 234 (0.43%)
    3 / 293 (1.02%)
    15 / 382 (3.93%)
         occurrences all number
    26
    27
    1
    3
    22
    Nasopharyngitis
         subjects affected / exposed
    29 / 382 (7.59%)
    32 / 381 (8.40%)
    2 / 234 (0.85%)
    2 / 293 (0.68%)
    26 / 382 (6.81%)
         occurrences all number
    33
    39
    2
    2
    29
    Viral upper respiratory tract infection
         subjects affected / exposed
    22 / 382 (5.76%)
    11 / 381 (2.89%)
    6 / 234 (2.56%)
    6 / 293 (2.05%)
    17 / 382 (4.45%)
         occurrences all number
    35
    15
    7
    6
    22
    Urinary tract infection
         subjects affected / exposed
    40 / 382 (10.47%)
    15 / 381 (3.94%)
    10 / 234 (4.27%)
    11 / 293 (3.75%)
    25 / 382 (6.54%)
         occurrences all number
    59
    22
    17
    11
    31
    Vulvovaginal candidiasis
         subjects affected / exposed
    30 / 382 (7.85%)
    10 / 381 (2.62%)
    7 / 234 (2.99%)
    7 / 293 (2.39%)
    19 / 382 (4.97%)
         occurrences all number
    41
    12
    7
    7
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jun 2011
    1. LCS12 extension phase was to continue up to 3 years, and was not to be ended if a marketing authorization was received. Phase between the screening visit and randomization visit was reduced to 8 weeks from the originally planned 12 weeks 2. Date of birth was removed from the population characteristics to be displayed; only age was used 3. Cervical smear: results evaluated with other systems corresponding to the Bethesda system were accepted 4. It was emphasized that the investigators had to be experienced with Intrauterine device (IUD)/ Intra-uterine delivery system (IUS) insertion, and that they must have attended the LCS12 insertion training given by the sponsor 5. The need to use back up contraception if switching from progestin only oral contraception or hormone releasing IUS to the study drug was added 6. The text describing the use of a condom or another barrier method for contraception at least 7 days before LCS12 removal was reworded. Instructions were included for both prematurely discontinuing subjects and for subjects who complete the study 7. Perforations were to be reported as serious adverse events 8. As the use of progestogen containing contraceptives may have an effect on peripheral insulin resistance and glucose tolerance, guidance on monitoring blood glucose concentration was added 9. A clarification was made regarding the reporting of pregnancies occurring after the end-of-study (EOS): In the LCS12 group, all pregnancies reported up to 12 months after EOS were followed up for the final outcome of the mother and fetus/child 10. Further clarification of the definition of dysmenorrhea as an AE was included 11. As women with presence or history of venous or arterial thrombotic/thromboembolic events were not allowed in the study, the sentence about making women with history of thromboembolic disorder aware of a possible reoccurrence was removed 12. Minor changes implemented to the text due to grammatical or typographical errors.

    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.
    Decimal places were automatically truncated if last decimal equals zero.
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