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    Clinical Trial Results:
    A multi-center, open label, single-arm study to investigate the safety and efficacy of daily oral administration of 2 mg dienogest tablets for the treatment of endometriosis in adolescents over a treatment period of 52 weeks

    Summary
    EudraCT number
    		 2009-017169-53
    Trial protocol
    		 ES   FI   DE   AT   FR   CZ  
    Global end of trial date
    12 Sep 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    04 Sep 2016
    First version publication date
    28 Jun 2015
    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
    BAY86-5258/13788
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01283724
    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-000147-PIP01-07
    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
    20 Dec 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the influence of long-term oral administration of dienogest 2 milligram (mg) once a day, on bone mineral density (BMD) of the spine, measured by dual-energy X-ray absorptiometry (DEXA) in adolescents with confirmed or clinically suspected endometriosis.
    Protection of trial subjects
    The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of this study, were designed to ensure that the sponsor and investigator abide by Good Clinical Practice guidelines, the Note for Guidance on Clinical Investigation of Medicinal Products in the Paediatric population (International Conference of Harmonization [ICH] topic E11 – Committee for Medicinal Products for Human Use (CHMP)/ICH/2711/99), and under the guiding principles detailed in the Declaration of Helsinki. As applicable according to local regulations, the protocol and all protocol amendments were reviewed and approved by each pertinent Competent Authority. Each subject and legal representative(s) or proxy consenter(s) had ample time and opportunity to ask questions and was informed about the right to withdraw from the study at any time without any disadvantage and without having to provide reasons for this decision. If at any time the subject had doubts or concerns regarding study procedures or investigations, the investigator had to stop the examination and had to take enough time to assess the reason and discuss the willingness of further participation with the subject. The subject entered the study only if the subject and legal representative(s) or proxy consenter(s) voluntarily agreed to sign the informed consent/ assent form and had done so. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug. The design of the study was discussed with and agreed by the Pediatric Committee of the European Medicines Agency.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Mar 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    Czech Republic: 50
    Country: Number of subjects enrolled
    Finland: 19
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 16
    Worldwide total number of subjects
    111
    EEA total number of subjects
    111
    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)
    111
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 21 study centers in 6 countries: Austria, Czech Republic, Finland, France, Germany, and Spain. Girls from menarche until less than 18 years of age were considered to be appropriate with confirmed or clinically suspected endometriosis were recruited.

    Pre-assignment
    Screening details
    		 Out of 120 subjects screened, 111 were assigned to treatment and 9 were listing-only subjects (LOS) who did not receive the treatment. Of these 9 LOS, 8 were screening failures and 1 subject withdrew from the study before start of treatment.

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

    Arms
    Arm title
    		 Dienogest (Visanne, BAY86-5258)
    Arm description
    		 Subjects received Dienogest tablet orally at a dosage of 2 mg once daily over a period of 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dienogest
    Investigational medicinal product code
    BAY86-5258
    Other name
    Visanne
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Dienogest tablet orally at a dosage of 2 mg once daily over a period of 52 weeks.

    Number of subjects in period 1
    		Dienogest (Visanne, BAY86-5258)
    Started
    111
    Received treatment
    111
    Entered Follow up period 1
    111
    Completed treatment
    97
    Completed
    97
    Not completed
    14
         Consent withdrawn by subject
    6
         Adverse event, non-fatal
    5
         Noncompliance with study drug
    1
         Lost to follow-up
    1
         Lack of efficacy
    1
    Period 2
    Period 2 title
    Follow-up period 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Dienogest (Visanne, BAY86-5258)
    Arm description
    		 Subjects received Dienogest tablet orally at a dosage of 2 mg once daily over a period of 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dienogest
    Investigational medicinal product code
    BAY86-5258
    Other name
    Visanne
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Dienogest tablet orally at a dosage of 2 mg once daily over a period of 52 weeks.

    Number of subjects in period 2 [1]
    		Dienogest (Visanne, BAY86-5258)
    Started
    61
    Completed
    61
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 111 subjects started Follow-up period 1 (a follow-up assessment of 4 weeks after the end of treatment) out of which 107 subjects completed and reasons for non-completion of 4 subjects were consent withdrawn in 2 subjects and lost to follow-up in 2 subjects. A total of 61 subjects with a decrease in BMD at the end of treatment, started and completed Follow-up period 2 (a follow-up assessment for 26 weeks after the end of treatment).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dienogest (Visanne, BAY86-5258)
    Reporting group description
    		 Subjects received Dienogest tablet orally at a dosage of 2 mg once daily over a period of 52 weeks.

    Reporting group values
    		 Dienogest (Visanne, BAY86-5258) Total
    Number of subjects
    		 111 111
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.4 ( 1.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 111 111
    Race
    Units: Subjects
        White
    		 105 105
        Black or African American
    		 1 1
        Not recorded
    		 5 5
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 105 105
        Hispanic or Latino
    		 1 1
        Not recorded
    		 5 5

    End points

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    End points reporting groups
    Reporting group title
    Dienogest (Visanne, BAY86-5258)
    Reporting group description
    		 Subjects received Dienogest tablet orally at a dosage of 2 mg once daily over a period of 52 weeks.
    Reporting group title
    Dienogest (Visanne, BAY86-5258)
    Reporting group description
    		 Subjects received Dienogest tablet orally at a dosage of 2 mg once daily over a period of 52 weeks.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS consisted of 111 subjects and was defined as the set of all subjects who took at least one unit of study drug and if at least one observation after drug administration was available.

    Primary: Relative Percent Change From Baseline in Spinal Lumbar Vertebrae 2 to 4 (L2-L4) Bone Mineral Density (BMD) at Week 52 Assessed by Dual-Energy X-ray Absorptiometry (DEXA)

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    End point title
    		 Relative Percent Change From Baseline in Spinal Lumbar Vertebrae 2 to 4 (L2-L4) Bone Mineral Density (BMD) at Week 52 Assessed by Dual-Energy X-ray Absorptiometry (DEXA) [1]
    End point description
    The measurement of BMD by DEXA is the gold standard method for investigation of bone mass.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    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: Statistical analysis was not performed since descriptive statistical analysis was only planned for this endpoint.
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    103 [2]
    Units: percent change
        arithmetic mean (standard deviation)
    -1.2 ( 2.3 )
    Notes
    [2] - FAS subjects with evaluable data for this endpoint.
    No statistical analyses for this end point

    Secondary: Relative Percent Change From Baseline in Whole Body Bone Mineral Density (BMD) at Week 52 Assessed by Dual-Energy X-ray Absorptiometry (DEXA)

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    End point title
    		 Relative Percent Change From Baseline in Whole Body Bone Mineral Density (BMD) at Week 52 Assessed by Dual-Energy X-ray Absorptiometry (DEXA)
    End point description
    The measurement of BMD by DEXA is the gold standard method for investigation of bone mass.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    102 [3]
    Units: percent change
        arithmetic mean (standard deviation)
    0.8 ( 1.6 )
    Notes
    [3] - FAS subjects with evaluable data for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Spinal Lumbar Vertebrae 2 to 4 (L2-L4) Z-scores at Week 52

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    End point title
    		 Change From Baseline in Spinal Lumbar Vertebrae 2 to 4 (L2-L4) Z-scores at Week 52
    End point description
    Based on the BMD values and the weight, the age-normalized percentiles (Z-scores) were determined to allow for comparison with historical control groups. “No difference” in comparison with the historical control groups was defined as a Z-score between '-0.5' and '0.5', a lower value was defined as a value below '-0.5', and a higher value above '0.5'.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    103 [4]
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.3188 ( 0.2649 )
    Notes
    [4] - FAS subjects with evaluable data for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Whole Body Z-scores at Week 52

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    End point title
    		 Change From Baseline in Whole Body Z-scores at Week 52
    End point description
    Based on the BMD values and the weight, the age-normalized percentiles (Z-scores) were determined to allow for comparison with historical control groups. “No difference” in comparison with the historical control groups was defined as a Z-score between '-0.5' and '0.5', a lower value was defined as a value below '-0.5', and a higher value above '0.5'.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    102 [5]
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.0609 ( 0.3181 )
    Notes
    [5] - FAS subjects with evaluable data for this endpoint.
    No statistical analyses for this end point

    Secondary: Percentage of Responders at Week 24

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    End point title
    		 Percentage of Responders at Week 24
    End point description
    Responders were defined as subjects with reduction in pain intensity from baseline of at least 30% in the Visual Analog Scale (VAS) at Week 24. VAS consisted of a 100 unit long straight line, with verbal anchors at either end, representing a continuum of pain intensity. One end of the line with 0 score as “absence of pain” while the other end of the line with 100 score as “unbearable pain”. The assessment of pelvic pain on a VAS was done once every 4 weeks till the end of the treatment (Week 52).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    100 [6]
    Units: Percentage of subjects
    number (not applicable)
        Yes
    81
        No
    19
    Notes
    [6] - FAS subjects with evaluable data for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pelvic Pain Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile

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    End point title
    		 Change From Baseline in Pelvic Pain Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile
    End point description
    The cardinal symptoms inlcuded in the modified Biberoglu and Behrman severity profile were pelvic pain, dysmenorrhea, and dyspareunia (the latter only in those subjects having sexual intercourse), analyzed at all visits with symptom severity scores from 0 (none) to 3 (severe). Negative value for change from baseline indicates an improvement. In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    110 [7]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 4 (N=107)
    -0.757 ( 0.9985 )
        Change at Week 8 (N=106)
    -1.0094 ( 0.971 )
        Change at Week 12 (N=103)
    -1.0291 ( 1.0333 )
        Change at Week 16 (N=100)
    -1.05 ( 1.0481 )
        Change at Week 20 (N=97)
    -1.0825 ( 0.9754 )
        Change at Week 24 (N=99)
    -1.2424 ( 0.9699 )
        Change at Week 28 (N=97)
    -1.2062 ( 0.9889 )
        Change at Week 32 (N=97)
    -1.2165 ( 1.0127 )
        Change at Week 36 (N=95)
    -1.2421 ( 1.0181 )
        Change at Week 40 (N=97)
    -1.3402 ( 0.967 )
        Change at Week 44 (N=94)
    -1.383 ( 0.9849 )
        Change at Week 48 (N=94)
    -1.4255 ( 0.8858 )
        Change at Week 52 (N=103)
    -1.3786 ( 0.9713 )
    Notes
    [7] - FAS subjects with baseline data for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Dysmenorrhea Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile

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    End point title
    		 Change From Baseline in Dysmenorrhea Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile
    End point description
    The cardinal symptoms inlcuded in the modified Biberoglu and Behrman severity profile were pelvic pain, dysmenorrhea, and dyspareunia (the latter only in those subjects having sexual intercourse), analyzed at all visits with symptom severity scores from 0 (none) to 3 (severe). Negative value for change from baseline indicates an improvement. In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    110 [8]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 4 (N=107)
    -0.7944 ( 1.1221 )
        Change at Week 8 (N=106)
    -1.3208 ( 1.1343 )
        Change at Week 12 (N=103)
    -1.4854 ( 1.1014 )
        Change at Week 16 (N=100)
    -1.43 ( 1.0565 )
        Change at Week 20 (N=97)
    -1.5876 ( 1.0483 )
        Change at Week 24 (N=99)
    -1.5657 ( 1.0016 )
        Change at Week 28 (N=97)
    -1.5361 ( 1.0314 )
        Change at Week 32 (N=97)
    -1.5773 ( 1.1165 )
        Change at Week 36 (N=95)
    -1.5579 ( 1.1914 )
        Change at Week 40 (N=97)
    -1.7113 ( 1.0304 )
        Change at Week 44 (N=94)
    -1.7447 ( 1.0363 )
        Change at Week 48 (N=94)
    -1.7447 ( 1.0466 )
        Change at Week 52 (N=103)
    -1.7379 ( 0.9596 )
    Notes
    [8] - FAS subjects with baseline data for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Dyspareunia Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile

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    End point title
    		 Change From Baseline in Dyspareunia Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile
    End point description
    The cardinal symptoms inlcuded in the modified Biberoglu and Behrman severity profile were pelvic pain, dysmenorrhea, and dyspareunia (the latter only in those subjects having sexual intercourse), analyzed at all visits with symptom severity scores from 0 (none) to 3 (severe). Subjects evaluated the cardinal symptoms using modified Biberoglu and Behrman severity profile in an e-diary over the whole treatment period. Negative value for change from baseline indicates an improvement. In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    21 [9]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change at Week 4 (N=13)
    -0.1538 ( 0.6887 )
        Change at Week 8 (N=15)
    -0.2667 ( 0.7988 )
        Change at Week 12 (N=15)
    -0.2667 ( 0.8837 )
        Change at Week 16 (N=17)
    -0.1765 ( 1.0744 )
        Change at Week 20 (N=15)
    -0.4 ( 0.8281 )
        Change at Week 24 (N=12)
    -0.25 ( 0.6216 )
        Change at Week 28 (N=13)
    -0.4615 ( 0.7763 )
        Change at Week 32 (N=14)
    -0.3571 ( 0.8419 )
        Change at Week 36 (N=13)
    -0.2308 ( 0.725 )
        Change at Week 40 (N=14)
    -0.3571 ( 0.7449 )
        Change at Week 44 (N=12)
    -0.5833 ( 1.0836 )
        Change at Week 48 (N=13)
    -0.4615 ( 1.45 )
        Change at Week 52 (N=13)
    -0.2308 ( 0.725 )
    Notes
    [9] - FAS subjects with baseline data for this endpoint.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Pelvic Pain Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile

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    End point title
    		 Percentage of Subjects With Pelvic Pain Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile
    End point description
    In order to judge therapeutic effectiveness and to compare subjects’ complaints, a severity profile score of pelvic pain was assessed using a rating scale: missing; 0 = none; 1 = mild (occasional pelvic discomfort); 2 = moderate (noticeable discomfort for most of the cycle); 3 = severe (requires strong analgesics and persists during cycle when not menstruating) based on the subject’s self-assessment of symptoms. In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    110 [10]
    Units: Percentage of subjects
    number (not applicable)
        Baseline (N=110): missing
    0
        Baseline (N=110): none
    9.1
        Baseline (N=110): mild
    23.6
        Baseline (N=110): moderate
    52.7
        Baseline (N=110): severe
    14.5
        Week 4 (N=108): missing
    0
        Week 4 (N=108): none
    35.2
        Week 4 (N=108): mild
    40.7
        Week 4 (N=108): moderate
    16.7
        Week 4 (N=108): severe
    7.4
        Week 8 (N=107): missing
    0
        Week 8 (N=107): none
    44.9
        Week 8 (N=107): mild
    42.1
        Week 8 (N=107): moderate
    8.4
        Week 8 (N=107): severe
    4.7
        Week 12 (N=104): missing
    0
        Week 12 (N=104): none
    53.8
        Week 12 (N=104): mild
    26
        Week 12 (N=104): moderate
    16.3
        Week 12 (N=104): severe
    3.8
        Week 16 (N=101): missing
    0
        Week 16 (N=101): none
    47.5
        Week 16 (N=101): mild
    38.6
        Week 16 (N=101): moderate
    12.9
        Week 16 (N=101): severe
    1
        Week 20 (N=98): missing
    0
        Week 20 (N=98): none
    48
        Week 20 (N=98): mild
    38.8
        Week 20 (N=98): moderate
    13.3
        Week 20 (N=98): severe
    0
        Week 24 (N=100): missing
    0
        Week 24 (N=100): none
    60
        Week 24 (N=100): mild
    30
        Week 24 (N=100): moderate
    7
        Week 24 (N=100): severe
    3
        Week 28 (N=98): missing
    0
        Week 28 (N=98): none
    57.1
        Week 28 (N=98): mild
    32.7
        Week 28 (N=98): moderate
    8.2
        Week 28 (N=98): severe
    2
        Week 32 (N=98): missing
    0
        Week 32 (N=98): none
    59.2
        Week 32 (N=98): mild
    31.6
        Week 32 (N=98): moderate
    6.1
        Week 32 (N=98): severe
    3.1
        Week 36 (N=96): missing
    0
        Week 36 (N=96): none
    61.5
        Week 36 (N=96): mild
    29.2
        Week 36 (N=96): moderate
    7.3
        Week 36 (N=96): severe
    2.1
        Week 40 (N=98): missing
    0
        Week 40 (N=98): none
    66.3
        Week 40 (N=98): mild
    29.6
        Week 40 (N=98): moderate
    3.1
        Week 40 (N=98): severe
    1
        Week 44 (N=95): missing
    0
        Week 44 (N=95): none
    69.5
        Week 44 (N=95): mild
    25.3
        Week 44 (N=95): moderate
    4.2
        Week 44 (N=95): severe
    1.1
        Week 48 (N=95): missing
    0
        Week 48 (N=95): none
    73.7
        Week 48 (N=95): mild
    23.2
        Week 48 (N=95): moderate
    3.2
        Week 48 (N=95): severe
    0
        Week 52 (N=104): missing
    0
        Week 52 (N=104): none
    71.2
        Week 52 (N=104): mild
    24
        Week 52 (N=104): moderate
    3.8
        Week 52 (N=104): severe
    1
    Notes
    [10] - FAS subjects with baseline data for this endpoint.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Dysmenorrhea Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile

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    End point title
    		 Percentage of Subjects With Dysmenorrhea Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile
    End point description
    In order to judge therapeutic effectiveness and to compare subjects’ complaints, a severity profile score of dysmenorrhea was assessed using a rating scale: missing; 0 = none; 1 = mild (some loss in work efficiency); 2 = moderate (in bed part of day, occasional loss of work efficiency); 3 = severe (in bed one or more days, incapacitation) based on the subject’s self-assessment of symptoms. In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    110 [11]
    Units: Percentage of subjects
    number (not applicable)
        Baseline (N=110): missing
    0
        Baseline (N=110): none
    3.6
        Baseline (N=110): mild
    21.8
        Baseline (N=110): moderate
    47.3
        Baseline (N=110): severe
    27.3
        Week 4 (N=108): missing
    0
        Week 4 (N=108): none
    30.6
        Week 4 (N=108): mild
    29.6
        Week 4 (N=108): moderate
    28.7
        Week 4 (N=108): severe
    11.1
        Week 8 (N=107): missing
    0
        Week 8 (N=107): none
    57
        Week 8 (N=107): mild
    20.6
        Week 8 (N=107): moderate
    21.5
        Week 8 (N=107): severe
    0.9
        Week 12 (N=104): missing
    0
        Week 12 (N=104): none
    62.5
        Week 12 (N=104): mild
    27.9
        Week 12 (N=104): moderate
    8.7
        Week 12 (N=104): severe
    1
        Week 16 (N=101): missing
    0
        Week 16 (N=101): none
    61.4
        Week 16 (N=101): mild
    25.7
        Week 16 (N=101): moderate
    12.9
        Week 16 (N=101): severe
    0
        Week 20 (N=98): missing
    0
        Week 20 (N=98): none
    73.5
        Week 20 (N=98): mild
    18.4
        Week 20 (N=98): moderate
    6.1
        Week 20 (N=98): severe
    2
        Week 24 (N=100): missing
    0
        Week 24 (N=100): none
    70
        Week 24 (N=100): mild
    20
        Week 24 (N=100): moderate
    8
        Week 24 (N=100): severe
    2
        Week 28 (N=98): missing
    0
        Week 28 (N=98): none
    69.4
        Week 28 (N=98): mild
    19.4
        Week 28 (N=98): moderate
    8.2
        Week 28 (N=98): severe
    3.1
        Week 32 (N=98): missing
    0
        Week 32 (N=98): none
    73.5
        Week 32 (N=98): mild
    17.3
        Week 32 (N=98): moderate
    6.1
        Week 32 (N=98): severe
    3.1
        Week 36 (N=96): missing
    0
        Week 36 (N=96): none
    71.9
        Week 36 (N=96): mild
    16.7
        Week 36 (N=96): moderate
    8.3
        Week 36 (N=96): severe
    3.1
        Week 40 (N=98): missing
    0
        Week 40 (N=98): none
    80.6
        Week 40 (N=98): mild
    12.2
        Week 40 (N=98): moderate
    6.1
        Week 40 (N=98): severe
    1
        Week 44 (N=95): missing
    0
        Week 44 (N=95): none
    76.8
        Week 44 (N=95): mild
    20
        Week 44 (N=95): moderate
    3.2
        Week 44 (N=95): severe
    0
        Week 48 (N=95): missing
    0
        Week 48 (N=95): none
    83.2
        Week 48 (N=95): mild
    11.6
        Week 48 (N=95): moderate
    4.2
        Week 48 (N=95): severe
    1.1
        Week 52 (N=104): missing
    0
        Week 52 (N=104): none
    78.8
        Week 52 (N=104): mild
    15.4
        Week 52 (N=104): moderate
    5.8
        Week 52 (N=104): severe
    0
    Notes
    [11] - FAS subjects with baseline data for this endpoint.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Dyspareunia Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile

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    End point title
    		 Percentage of Subjects With Dyspareunia Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile
    End point description
    In order to judge therapeutic effectiveness and to compare subjects’ complaints, a severity profile score of dyspareunia was assessed using a rating scale: missing; 0 = none (no pain during intercourse); 1 = mild (tolerated discomfort); 2 = moderate (intercourse painful to the point of causing interdiction); 3 = severe (avoids intercourse because of pain) based on the subject’s self-assessment of symptoms. In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    110 [12]
    Units: Percentage of subjects
    number (not applicable)
        Baseline (N=110): missing
    80.9
        Baseline (N=110): none
    9.1
        Baseline (N=110): mild
    5.5
        Baseline (N=110): moderate
    3.6
        Baseline (N=110): severe
    0.9
        Week 4 (N=108): missing
    80.6
        Week 4 (N=108): none
    12
        Week 4 (N=108): mild
    3.7
        Week 4 (N=108): moderate
    3.7
        Week 4 (N=108): severe
    0
        Week 8 (N=107): missing
    75.7
        Week 8 (N=107): none
    15
        Week 8 (N=107): mild
    6.5
        Week 8 (N=107): moderate
    2.8
        Week 8 (N=107): severe
    0
        Week 12 (N=104): missing
    74
        Week 12 (N=104): none
    16.3
        Week 12 (N=104): mild
    7.7
        Week 12 (N=104): moderate
    1.9
        Week 12 (N=104): severe
    0
        Week 16 (N=101): missing
    71.3
        Week 16 (N=101): none
    16.8
        Week 16 (N=101): mild
    6.9
        Week 16 (N=101): moderate
    4
        Week 16 (N=101): severe
    1
        Week 20 (N=98): missing
    70.4
        Week 20 (N=98): none
    19.4
        Week 20 (N=98): mild
    7.1
        Week 20 (N=98): moderate
    3.1
        Week 20 (N=98): severe
    0
        Week 24 (N=100): missing
    75
        Week 24 (N=100): none
    18
        Week 24 (N=100): mild
    4
        Week 24 (N=100): moderate
    3
        Week 24 (N=100): severe
    0
        Week 28 (N=98): missing
    73.5
        Week 28 (N=98): none
    18.4
        Week 28 (N=98): mild
    5.1
        Week 28 (N=98): moderate
    3.1
        Week 28 (N=98): severe
    0
        Week 32 (N=98): missing
    65.3
        Week 32 (N=98): none
    25.5
        Week 32 (N=98): mild
    6.1
        Week 32 (N=98): moderate
    3.1
        Week 32 (N=98): severe
    0
        Week 36 (N=96): missing
    63.5
        Week 36 (N=96): none
    24
        Week 36 (N=96): mild
    7.3
        Week 36 (N=96): moderate
    5.2
        Week 36 (N=96): severe
    0
        Week 40 (N=98): missing
    68.4
        Week 40 (N=98): none
    20.4
        Week 40 (N=98): mild
    7.1
        Week 40 (N=98): moderate
    2
        Week 40 (N=98): severe
    2
        Week 44 (N=95): missing
    63.2
        Week 44 (N=95): none
    23.2
        Week 44 (N=95): mild
    10.5
        Week 44 (N=95): moderate
    2.1
        Week 44 (N=95): severe
    1.1
        Week 48 (N=95): missing
    64.2
        Week 48 (N=95): none
    28.4
        Week 48 (N=95): mild
    4.2
        Week 48 (N=95): moderate
    1.1
        Week 48 (N=95): severe
    2.1
        Week 52 (N=104): missing
    66.3
        Week 52 (N=104): none
    23.1
        Week 52 (N=104): mild
    4.8
        Week 52 (N=104): moderate
    3.8
        Week 52 (N=104): severe
    1.9
    Notes
    [12] - FAS subjects with baseline data for this endpoint.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Pelvic Tenderness Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile

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    End point title
    		 Percentage of Subjects With Pelvic Tenderness Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile
    End point description
    In order to judge therapeutic effectiveness and to compare subjects’ complaints, a severity profile score of pelvic tenderness was assessed using a rating scale: missing; 0 = none (no pain during intercourse); 1 = mild (minimal tenderness on palpation); 2 = moderate (extensive tenderness on palpation); 3 = severe (unable to palpate because of tenderness) based on the gynecological palpation by the attending physician. In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    111 [13]
    Units: Percentage of subjects
    number (not applicable)
        Baseline (N=33): missing
    0
        Baseline (N=33): none
    63.6
        Baseline (N=33): mild
    30.3
        Baseline (N=33): moderate
    6.1
        Baseline (N=33): severe
    0
        Week 4 (N=39): missing
    0
        Week 4 (N=39): none
    66.7
        Week 4 (N=39): mild
    28.2
        Week 4 (N=39): moderate
    5.1
        Week 4 (N=39): severe
    0
        Week 8 (N=45): missing
    0
        Week 8 (N=45): none
    64.4
        Week 8 (N=45): mild
    28.9
        Week 8 (N=45): moderate
    6.7
        Week 8 (N=45): severe
    0
        Week 12 (N=48): missing
    0
        Week 12 (N=48): none
    77.1
        Week 12 (N=48): mild
    18.8
        Week 12 (N=48): moderate
    4.2
        Week 12 (N=48): severe
    0
        Week 16 (N=43): missing
    0
        Week 16 (N=43): none
    79.1
        Week 16 (N=43): mild
    18.6
        Week 16 (N=43): moderate
    2.3
        Week 16 (N=43): severe
    0
        Week 20 (N=38): missing
    0
        Week 20 (N=38): none
    89.5
        Week 20 (N=38): mild
    7.9
        Week 20 (N=38): moderate
    2.6
        Week 20 (N=38): severe
    0
        Week 24 (N=53): missing
    0
        Week 24 (N=53): none
    83
        Week 24 (N=53): mild
    15.1
        Week 24 (N=53): moderate
    1.9
        Week 24 (N=53): severe
    0
        Week 28 (N=40): missing
    0
        Week 28 (N=40): none
    87.5
        Week 28 (N=40): mild
    12.5
        Week 28 (N=40): moderate
    0
        Week 28 (N=40): severe
    0
        Week 32 (N=37): missing
    0
        Week 32 (N=37): none
    91.9
        Week 32 (N=37): mild
    8.1
        Week 32 (N=37): moderate
    0
        Week 32 (N=37): severe
    0
        Week 36 (N=46): missing
    0
        Week 36 (N=46): none
    89.1
        Week 36 (N=46): mild
    6.5
        Week 36 (N=46): moderate
    4.3
        Week 36 (N=46): severe
    0
        Week 40 (N=38): missing
    0
        Week 40 (N=38): none
    86.8
        Week 40 (N=38): mild
    13.2
        Week 40 (N=38): moderate
    0
        Week 40 (N=38): severe
    0
        Week 44 (N=39): missing
    0
        Week 44 (N=39): none
    87.2
        Week 44 (N=39): mild
    10.3
        Week 44 (N=39): moderate
    2.6
        Week 44 (N=39): severe
    0
        Week 48 (N=38): missing
    0
        Week 48 (N=38): none
    94.7
        Week 48 (N=38): mild
    5.3
        Week 48 (N=38): moderate
    0
        Week 48 (N=38): severe
    0
        Week 52 (N=56): missing
    0
        Week 52 (N=56): none
    80.4
        Week 52 (N=56): mild
    17.9
        Week 52 (N=56): moderate
    1.8
        Week 52 (N=56): severe
    0
    Notes
    [13] - FAS.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Induration Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile

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    End point title
    		 Percentage of Subjects With Induration Over 52 Weeks Using Modified Biberoglu and Behrman Severity Profile
    End point description
    In order to judge therapeutic effectiveness and to compare subjects’ complaints, a severity profile score of induration was assessed using a rating scale: missing; 0 = none (no pain during intercourse); 1 = mild (uterus freely mobile, induration in the cul-de-sac); 2 = moderate (thickened and indurated adnexa and cul-de-sac, restricted uterine mobility); 3 = severe (nodular adnexa and cul-de-sac, uterus frequently frozen) based on the gynecological palpation by the attending physician. In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    111 [14]
    Units: Percentage of subjects
    number (not applicable)
        Baseline (N=33): missing
    24.2
        Baseline (N=33): none
    60.6
        Baseline (N=33): mild
    15.2
        Baseline (N=33): moderate
    0
        Baseline (N=33): severe
    0
        Week 4 (N=39): missing
    20.5
        Week 4 (N=39): none
    71.8
        Week 4 (N=39): mild
    7.7
        Week 4 (N=39): moderate
    0
        Week 4 (N=39): severe
    0
        Week 8 (N=45): missing
    22.2
        Week 8 (N=45): none
    68.9
        Week 8 (N=45): mild
    8.9
        Week 8 (N=45): moderate
    0
        Week 8 (N=45): severe
    0
        Week 12 (N=48): missing
    18.8
        Week 12 (N=48): none
    81.3
        Week 12 (N=48): mild
    0
        Week 12 (N=48): moderate
    0
        Week 12 (N=48): severe
    0
        Week 16 (N=43): missing
    18.6
        Week 16 (N=43): none
    79.1
        Week 16 (N=43): mild
    2.3
        Week 16 (N=43): moderate
    0
        Week 16 (N=43): severe
    0
        Week 20 (N=38): missing
    21.1
        Week 20 (N=38): none
    78.9
        Week 20 (N=38): mild
    0
        Week 20 (N=38): moderate
    0
        Week 20 (N=38): severe
    0
        Week 24 (N=53): missing
    18.9
        Week 24 (N=53): none
    75.5
        Week 24 (N=53): mild
    5.7
        Week 24 (N=53): moderate
    0
        Week 24 (N=53): severe
    0
        Week 28 (N=40): missing
    20
        Week 28 (N=40): none
    80
        Week 28 (N=40): mild
    0
        Week 28 (N=40): moderate
    0
        Week 28 (N=40): severe
    0
        Week 32 (N=37): missing
    18.9
        Week 32 (N=37): none
    81.1
        Week 32 (N=37): mild
    0
        Week 32 (N=37): moderate
    0
        Week 32 (N=37): severe
    0
        Week 36 (N=46): missing
    19.6
        Week 36 (N=46): none
    78.3
        Week 36 (N=46): mild
    2.2
        Week 36 (N=46): moderate
    0
        Week 36 (N=46): severe
    0
        Week 40 (N=38): missing
    21.1
        Week 40 (N=38): none
    78.9
        Week 40 (N=38): mild
    0
        Week 40 (N=38): moderate
    0
        Week 40 (N=38): severe
    0
        Week 44 (N=39): missing
    20.5
        Week 44 (N=39): none
    79.5
        Week 44 (N=39): mild
    0
        Week 44 (N=39): moderate
    0
        Week 44 (N=39): severe
    0
        Week 48 (N=38): missing
    18.4
        Week 48 (N=38): none
    78.9
        Week 48 (N=38): mild
    2.6
        Week 48 (N=38): moderate
    0
        Week 48 (N=38): severe
    0
        Week 52 (N=56): missing
    10.7
        Week 52 (N=56): none
    87.5
        Week 52 (N=56): mild
    1.8
        Week 52 (N=56): moderate
    0
        Week 52 (N=56): severe
    0
    Notes
    [14] - FAS.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Global Impression (CGI) Scores - Assessed by the Investigator

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    End point title
    		 Percentage of Subjects With Clinical Global Impression (CGI) Scores - Assessed by the Investigator
    End point description
    The investigator rating scale used in this study was based on the validated CGI scale, which is widely used as a simple tool to assess the overall effect of treatments. The investigator or a sub-investigator rated the total improvement according to the following scale: Score 1 = very much improved; Score 2 = much improved; Score 3 = minimally improved; Score 4 = no change; Score 5 = minimally worse; Score 6 = much worse; Score 7 = very much worse. None of the subjects reported Score 7. In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24, 36, and 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    111 [15]
    Units: Percentage of subjects
    number (not applicable)
        Week 12 (N=104): Score=1
    39.4
        Week 12 (N=104): Score=2
    46.2
        Week 12 (N=104): Score=3
    10.6
        Week 12 (N=104): Score=4
    2.9
        Week 12 (N=104): Score=5
    1
        Week 12 (N=104): Score=6
    0
        Week 24 (N=102): Score=1
    64.7
        Week 24 (N=102): Score=2
    27.5
        Week 24 (N=102): Score=3
    5.9
        Week 24 (N=102): Score=4
    2
        Week 24 (N=102): Score=5
    0
        Week 24 (N=102): Score=6
    0
        Week 36 (N=98): Score=1
    67.3
        Week 36 (N=98): Score=2
    24.5
        Week 36 (N=98): Score=3
    6.1
        Week 36 (N=98): Score=4
    0
        Week 36 (N=98): Score=5
    1
        Week 36 (N=98): Score=6
    1
        Week 52 (N=109): Score=1
    64.2
        Week 52 (N=109): Score=2
    25.7
        Week 52 (N=109): Score=3
    4.6
        Week 52 (N=109): Score=4
    3.7
        Week 52 (N=109): Score=5
    1.8
        Week 52 (N=109): Score=6
    0
    Notes
    [15] - FAS.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinical Global Impression (CGI) Scores - Assessed by the Subject

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    End point title
    		 Percentage of Subjects With Clinical Global Impression (CGI) Scores - Assessed by the Subject
    End point description
    The subject rating scale used in this study was based on the validated CGI scale, which is widely used as a simple tool to assess the overall effect of treatments. The subject was asked to rate her satisfaction with the study treatment according to the following scale: Score 1 = very much satisfied; Score 2 = much satisfied; Score 3 = minimally satisfied; Score 4 = neither satisfied nor dissatisfied; Score 5 = minimally dissatisfied; Score 6 = much dissatisfied; Score 7 = very much dissatisfied. In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24, 36, 40, and 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    111 [16]
    Units: Percentage of subjects
    number (not applicable)
        Week 12 (N=104): Score=1
    27.9
        Week 12 (N=104): Score=2
    46.2
        Week 12 (N=104): Score=3
    15.4
        Week 12 (N=104): Score=4
    5.8
        Week 12 (N=104): Score=5
    1.9
        Week 12 (N=104): Score=6
    1.9
        Week 12 (N=104): Score=7
    1
        Week 24 (N=100): Score=1
    39
        Week 24 (N=100): Score=2
    45
        Week 24 (N=100): Score=3
    8
        Week 24 (N=100): Score=4
    6
        Week 24 (N=100): Score=5
    2
        Week 24 (N=100): Score=6
    0
        Week 24 (N=100): Score=7
    0
        Week 36 (N=96): Score=1
    44.8
        Week 36 (N=96): Score=2
    40.6
        Week 36 (N=96): Score=3
    10.4
        Week 36 (N=96): Score=4
    3.1
        Week 36 (N=96): Score=5
    0
        Week 36 (N=96): Score=6
    1
        Week 36 (N=96): Score=7
    0
        Week 40 (N=1): Score=1
    0
        Week 40 (N=1): Score=2
    100
        Week 40 (N=1): Score=3
    0
        Week 40 (N=1): Score=4
    0
        Week 40 (N=1): Score=5
    0
        Week 40 (N=1): Score=6
    0
        Week 40 (N=1): Score=7
    0
        Week 52 (N=103): Score=1
    47.6
        Week 52 (N=103): Score=2
    36.9
        Week 52 (N=103): Score=3
    8.7
        Week 52 (N=103): Score=4
    4.9
        Week 52 (N=103): Score=5
    0
        Week 52 (N=103): Score=6
    1.9
        Week 52 (N=103): Score=7
    0
    Notes
    [16] - FAS.
    No statistical analyses for this end point

    Other pre-specified: Number of Safety-related Findings

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    End point title
    		 Number of Safety-related Findings
    End point description
    Safety-related findings such as blood pressure, heart rate, body weight, and laboratory examinations, were listed as adverse events.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 2 days after last dose of study drug (approximately 52 weeks)
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    0 [17]
    Units: Findings
    Notes
    [17] - Data for this endpoint were reported in adverse event (AE) section of the study.
    No statistical analyses for this end point

    Other pre-specified: Vaginal Bleeding Events by 90-day Reference Period

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    End point title
    		 Vaginal Bleeding Events by 90-day Reference Period
    End point description
    Bleeding episodes were described using the reference period (RP) method recommended by the World Health Organization over a RP of 90 days. Each subject recorded the vaginal bleeding patterns in their e-diaries. In the listed categories, 'N' signifies those subjects who were evaluable for this measure.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    111 [18]
    Units: Events
    arithmetic mean (standard deviation)
        Bleeding /spotting episodes in RP-1 (N=64)
    3.1 ( 2.3 )
        Bleeding /spotting episodes in RP-2 (N=51)
    1.9 ( 2.1 )
        Bleeding /spotting episodes in RP-3 (N=55)
    1.5 ( 2.1 )
        Bleeding /spotting episodes in RP-4 (N=44)
    1.6 ( 2 )
    Notes
    [18] - FAS.
    No statistical analyses for this end point

    Other pre-specified: Number of Women With Pregnancy Test Result Over 52 Weeks

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    End point title
    		 Number of Women With Pregnancy Test Result Over 52 Weeks
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, unscheduled visit, and 52
    End point values
    		 Dienogest (Visanne, BAY86-5258)
    Number of subjects analysed
    111 [19]
    Units: Subjects
        Baseline (N=111): Positive
    0
        Baseline (N=111): Negative
    111
        Week 4 (N=110): Positive
    0
        Week 4 (N=110): Negative
    110
        Week 8 (N=107): Positive
    0
        Week 8 (N=107): Negative
    107
        Week 12 (N=104): Positive
    0
        Week 12 (N=104): Negative
    104
        Week 16 (N=103): Positive
    0
        Week 16 (N=103): Negative
    103
        Week 20 (N=100): Positive
    0
        Week 20 (N=100): Negative
    100
        Week 24 (N=102): Positive
    0
        Week 24 (N=102): Negative
    102
        Week 28 (N=100): Positive
    0
        Week 28 (N=100): Negative
    100
        Week 32 (N=97): Positive
    0
        Week 32 (N=97): Negative
    97
        Week 36 (N=99): Positive
    0
        Week 36 (N=99): Negative
    99
        Week 40 (N=97): Positive
    0
        Week 40 (N=97): Negative
    97
        Week 44 (N=97): Positive
    0
        Week 44 (N=97): Negative
    97
        Week 48 (N=95): Positive
    0
        Week 48 (N=95): Negative
    95
        Unscheduled visit (N=4): Positive
    1
        Unscheduled visit (N=4): Negative
    3
        Week 52 (N=108): Positive
    0
        Week 52 (N=108): Negative
    108
    Notes
    [19] - FAS.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 2 days after last dose of study drug (approximately 52 weeks)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Dienogest (BAY 86-5258)
    Reporting group description
    		 Subjects received Dienogest orally at a dosage of 2 mg once daily over a period of 52 weeks.

    Serious adverse events
    		 Dienogest (BAY 86-5258)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 111 (4.50%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Spinal column injury
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenomyosis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian adhesion
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pyelonephritis acute
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Dienogest (BAY 86-5258)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    92 / 111 (82.88%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Surgical and medical procedures
    Dental operation
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Orthodontic procedure
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Tooth repair
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Tonsillectomy
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Wisdom teeth removal
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Chills
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Discomfort
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Medical device pain
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    6 / 111 (5.41%)
         occurrences all number
    6
    Fatigue
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Malaise
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Irritability
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    3
    Influenza like illness
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Feeling cold
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    4 / 111 (3.60%)
         occurrences all number
    4
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Polycystic ovaries
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Pelvic pain
         subjects affected / exposed
    4 / 111 (3.60%)
         occurrences all number
    4
    Ovarian cyst
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Metrorrhagia
         subjects affected / exposed
    7 / 111 (6.31%)
         occurrences all number
    8
    Breast enlargement
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Menorrhagia
         subjects affected / exposed
    4 / 111 (3.60%)
         occurrences all number
    4
    Endometriosis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Endometrial hypertrophy
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Breast pain
         subjects affected / exposed
    8 / 111 (7.21%)
         occurrences all number
    9
    Menstruation irregular
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Vulvovaginal pruritus
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Vaginal inflammation
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Vaginal haemorrhage
         subjects affected / exposed
    4 / 111 (3.60%)
         occurrences all number
    7
    Vaginal discharge
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Uterine haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    3
    Oropharyngeal pain
         subjects affected / exposed
    6 / 111 (5.41%)
         occurrences all number
    12
    Nasal inflammation
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    6 / 111 (5.41%)
         occurrences all number
    7
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Tearfulness
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Panic disorder
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Mood swings
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    7
    Mood altered
         subjects affected / exposed
    4 / 111 (3.60%)
         occurrences all number
    4
    Depression
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Depressed mood
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    10
    Anxiety
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Libido decreased
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Body temperature increased
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    3
    Blood sodium increased
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    10 / 111 (9.01%)
         occurrences all number
    10
    White blood cell count increased
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Face injury
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Muscle strain
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    3
    Excoriation
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Sunburn
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Ligament sprain
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Ligament injury
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Hand fracture
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Arthropod bite
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Post-traumatic pain
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Procedural pain
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Tooth fracture
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    3
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Nervous system disorders
    Poor quality sleep
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    3
    Somnolence
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Migraine
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    7
    Hypoaesthesia
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    36 / 111 (32.43%)
         occurrences all number
    75
    Syncope
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Lymphadenitis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Myopia
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Haematochezia
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Glossitis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Gastritis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    8 / 111 (7.21%)
         occurrences all number
    9
    Diarrhoea
         subjects affected / exposed
    9 / 111 (8.11%)
         occurrences all number
    9
    Constipation
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    5 / 111 (4.50%)
         occurrences all number
    6
    Abdominal pain lower
         subjects affected / exposed
    7 / 111 (6.31%)
         occurrences all number
    10
    Flatulence
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Rectal haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Plicated tongue
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Odynophagia
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    13 / 111 (11.71%)
         occurrences all number
    18
    Hyperchlorhydria
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Haemorrhoids
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Gastric disorder
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    16 / 111 (14.41%)
         occurrences all number
    22
    Toothache
         subjects affected / exposed
    4 / 111 (3.60%)
         occurrences all number
    5
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    5 / 111 (4.50%)
         occurrences all number
    6
    Seborrhoea
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Rash pruritic
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Rash papular
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    3
    Alopecia
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Eczema
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Cafe au lait spots
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Blister
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Psoriasis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Torticollis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Neck pain
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    6 / 111 (5.41%)
         occurrences all number
    12
    Tendonitis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    2
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Acute tonsillitis
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    3
    Bronchitis
         subjects affected / exposed
    6 / 111 (5.41%)
         occurrences all number
    6
    Candidiasis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Chronic tonsillitis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Cystitis
         subjects affected / exposed
    8 / 111 (7.21%)
         occurrences all number
    8
    Ear infection
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    4
    Fungal skin infection
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    16 / 111 (14.41%)
         occurrences all number
    17
    Nasopharyngitis
         subjects affected / exposed
    35 / 111 (31.53%)
         occurrences all number
    61
    Otitis externa
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    2
    Gingivitis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Periodontitis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    7 / 111 (6.31%)
         occurrences all number
    8
    Gastroenteritis
         subjects affected / exposed
    4 / 111 (3.60%)
         occurrences all number
    5
    Gastroenteritis viral
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Otitis media acute
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    5 / 111 (4.50%)
         occurrences all number
    8
    Pneumonia
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Pyelonephritis acute
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    3 / 111 (2.70%)
         occurrences all number
    3
    Scarlet fever
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    5 / 111 (4.50%)
         occurrences all number
    5
    Tonsillitis
         subjects affected / exposed
    12 / 111 (10.81%)
         occurrences all number
    13
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Vaginal infection
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Varicella
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Adenovirus infection
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Helminthic infection
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    3
    Vulvitis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    2 / 111 (1.80%)
         occurrences all number
    4
    Burn infection
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Tinea versicolour
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    5 / 111 (4.50%)
         occurrences all number
    8
    Oral herpes
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1
    Lactose intolerance
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Dec 2010
    In the initial study protocol, the study phase was termed as “Phase IV”. The Austrian Health Authority (AGES) recommended a change of the study phase as “Phase II” in order to increase the focus on the latter aspects of the trial design.
    19 May 2011
    The following modifications were done in this protocol amendment: 1. Country specific change of inclusion criterion for Finland included study enrolment of 12 – 14 years old adolescents whose diagnosis of endometriosis had been confirmed by laparoscopy 2. Country specific change of requirements to perform gynecological examination in subjects below 15 years of age and written authorization of investigators
    16 Aug 2012
    Subjects with a decrease in BMD between baseline and end of treatment were invited for a follow-up scan of 6 months after the end of treatment in order to assess development of BMD after stopping study treatment. Data related to potential confounding parameters (height, weight, diet and medication) were also collected. A newly introduced Visit 17 was only to take place if there was a decrease in the lumbar spine BMD observed between Baseline (Visit 2) and End of Treatment (Visit 15). Introduced with this amendment, additional diagnostic procedures including a further BMD measurement of 12 months after end of treatment, and treatments were initiated as deemed necessary by the investigator.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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