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    Clinical Trial Results:
    A randomized, placebo-controlled, double-blind, parallel-group, multi-center, exploratory dose-response study to assess the efficacy and safety of different oral doses of BAY1128688 in women with symptomatic endometriosis over a 12-week treatment period

    Summary
    EudraCT number
    		 2017-000244-18
    Trial protocol
    		 GB   ES   HU   FI   CZ   AT   DE   BE   DK   NL   PL   IT  
    Global end of trial date
    22 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Oct 2019
    First version publication date
    18 Oct 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY1128688/17472
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03373422
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    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
    22 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to explore the dose response relationship of different doses of BAY1128688 compared to placebo in the treatment of endometriosis-related symptoms over a 12-week treatment period.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. 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
    30 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Czech Republic: 23
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 33
    Worldwide total number of subjects
    121
    EEA total number of subjects
    121
    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)
    121
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at multiple centers in 13 countries worldwide between 30 NOV 2017 (first subject first visit) and 22 OCT 2018 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall 230 subjects were screened of which 89 (39%) were screening failures. 141 subjects entered the pre-treatment period and were randomized, 20 randomized subjects dropped out before receiving the first dose of the study drug, therefore, 121 subjects were treated (enrolled).

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Tablet identical in appearance to BAY1128688; one tablet in the morning and one tablet in the evening
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo, for 12 weeks

    Arm title
    		 BAY1128688 3 mg once daily (OD)
    Arm description
    		 Subjects received one 3 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY1128688
    Investigational medicinal product code
    BAY1128688
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3 mg once daily (OD), Plus one placebo OD. Oral, 12 weeks (84 days)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo, for 12 weeks

    Arm title
    		 BAY1128688 10 mg OD
    Arm description
    		 Subjects received one 10 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY1128688
    Investigational medicinal product code
    BAY1128688
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily (OD), Plus one placebo OD. Oral, 12 weeks (84 days)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo, for 12 weeks

    Arm title
    		 BAY1128688 30 mg OD
    Arm description
    		 Subjects received one 30 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY1128688
    Investigational medicinal product code
    BAY1128688
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg once daily (OD), Plus one placebo OD. Oral, 12 weeks (84 days)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo, for 12 weeks

    Arm title
    		 BAY1128688 30 mg twice daily (BID)
    Arm description
    		 Subjects received one 30 mg BAY1128688 tablet in the morning and one 30 mg BAY1128688 tablet in the evening
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY1128688
    Investigational medicinal product code
    BAY1128688
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg twice daily (BID), 12 weeks (84 days)

    Arm title
    		 BAY1128688 60 mg BID
    Arm description
    		 Subjects received one 60 mg BAY1128688 tablet in the morning and one 60 mg BAY1128688 tablet in the evening
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY1128688
    Investigational medicinal product code
    BAY1128688
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    60 mg twice daily (BID), 12 weeks (84 days)

    Number of subjects in period 1
    		Placebo BAY1128688 3 mg once daily (OD) BAY1128688 10 mg OD BAY1128688 30 mg OD BAY1128688 30 mg twice daily (BID) BAY1128688 60 mg BID
    Started
    31
    11
    31
    10
    11
    27
    Included in PPS
    26
    11
    27
    9
    11
    20
    Completed
    12
    4
    14
    5
    4
    11
    Not completed
    19
    7
    17
    5
    7
    16
         Consent withdrawn by subject
    1
    -
    -
    -
    -
    2
         Physician decision
    -
    -
    -
    -
    -
    1
         Adverse Event
    -
    -
    1
    -
    2
    1
         Study Terminated by Sponsor
    17
    6
    16
    5
    5
    11
         Lack of efficacy
    1
    1
    -
    -
    -
    -
         Protocol deviation
    -
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Tablet identical in appearance to BAY1128688; one tablet in the morning and one tablet in the evening

    Reporting group title
    BAY1128688 3 mg once daily (OD)
    Reporting group description
    		 Subjects received one 3 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening

    Reporting group title
    BAY1128688 10 mg OD
    Reporting group description
    		 Subjects received one 10 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening

    Reporting group title
    BAY1128688 30 mg OD
    Reporting group description
    		 Subjects received one 30 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening

    Reporting group title
    BAY1128688 30 mg twice daily (BID)
    Reporting group description
    		 Subjects received one 30 mg BAY1128688 tablet in the morning and one 30 mg BAY1128688 tablet in the evening

    Reporting group title
    BAY1128688 60 mg BID
    Reporting group description
    		 Subjects received one 60 mg BAY1128688 tablet in the morning and one 60 mg BAY1128688 tablet in the evening

    Reporting group values
    		 Placebo BAY1128688 3 mg once daily (OD) BAY1128688 10 mg OD BAY1128688 30 mg OD BAY1128688 30 mg twice daily (BID) BAY1128688 60 mg BID Total
    Number of subjects
    		 31 11 31 10 11 27 121
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.39 ( 5.70 ) 32.45 ( 9.22 ) 32.65 ( 6.07 ) 32.90 ( 4.93 ) 33.45 ( 5.43 ) 31.33 ( 7.33 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 31 11 31 10 11 27 121
        Male
    		 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Tablet identical in appearance to BAY1128688; one tablet in the morning and one tablet in the evening

    Reporting group title
    BAY1128688 3 mg once daily (OD)
    Reporting group description
    		 Subjects received one 3 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening

    Reporting group title
    BAY1128688 10 mg OD
    Reporting group description
    		 Subjects received one 10 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening

    Reporting group title
    BAY1128688 30 mg OD
    Reporting group description
    		 Subjects received one 30 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening

    Reporting group title
    BAY1128688 30 mg twice daily (BID)
    Reporting group description
    		 Subjects received one 30 mg BAY1128688 tablet in the morning and one 30 mg BAY1128688 tablet in the evening

    Reporting group title
    BAY1128688 60 mg BID
    Reporting group description
    		 Subjects received one 60 mg BAY1128688 tablet in the morning and one 60 mg BAY1128688 tablet in the evening

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized subjects treated with at least one dose of study drug

    Subject analysis set title
    Per-protocol set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomized subjects without validity findings affecting the primary efficacy analysis

    Primary: Absolute change in mean pain of the 7 days with worst endometriosis-associated pelvic pain (EAPP) from baseline to end of treatment

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    End point title
    		 Absolute change in mean pain of the 7 days with worst endometriosis-associated pelvic pain (EAPP) from baseline to end of treatment [1]
    End point description
    This endpoint was analyzed with PPS
    End point type
    Primary
    End point timeframe
    From baseline to end of treatment (last 28 days of the treatment period, Days 57 - 84)
    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
    		 Placebo BAY1128688 3 mg once daily (OD) BAY1128688 10 mg OD BAY1128688 30 mg OD BAY1128688 30 mg twice daily (BID) BAY1128688 60 mg BID
    Number of subjects analysed
    11 [2]
    5 [3]
    11 [4]
    5 [5]
    5 [6]
    8 [7]
    Units: scores
        arithmetic mean (standard deviation)
    -2.03 ( 2.45 )
    -1.51 ( 1.74 )
    -2.14 ( 1.79 )
    -3.74 ( 1.56 )
    -2.40 ( 1.23 )
    -2.29 ( 1.58 )
    Notes
    [2] - PPS
    [3] - PPS
    [4] - PPS
    [5] - PPS
    [6] - PPS
    [7] - PPS
    No statistical analyses for this end point

    Secondary: Incidence of treatment-emergent adverse events

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    End point title
    		 Incidence of treatment-emergent adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    From start of the study drug until the end of the follow-up period
    End point values
    		 Placebo BAY1128688 3 mg once daily (OD) BAY1128688 10 mg OD BAY1128688 30 mg OD BAY1128688 30 mg twice daily (BID) BAY1128688 60 mg BID
    Number of subjects analysed
    31
    11
    31
    10
    11
    27
    Units: Subjects
    20
    5
    10
    9
    6
    21
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of the study drug until the end of the follow-up period
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Tablet identical in appearance to BAY1128688; one tablet in the morning and one tablet in the evening

    Reporting group title
    BAY1128688 3 mg once daily (OD)
    Reporting group description
    		 Subjects received one 3 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening

    Reporting group title
    BAY1128688 10 mg OD
    Reporting group description
    		 Subjects received one 10 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening

    Reporting group title
    BAY1128688 60 mg BID
    Reporting group description
    		 Subjects received one 60 mg BAY1128688 tablet in the morning and one 60 mg BAY1128688 tablet in the evening

    Reporting group title
    BAY1128688 30 mg OD
    Reporting group description
    		 Subjects received one 30 mg BAY1128688 tablet in the morning, and one placebo tablet in the evening

    Reporting group title
    BAY1128688 30 mg twice daily (BID)
    Reporting group description
    		 Subjects received one 30 mg BAY1128688 tablet in the morning and one 30 mg BAY1128688 tablet in the evening

    Serious adverse events
    		 Placebo BAY1128688 3 mg once daily (OD) BAY1128688 10 mg OD BAY1128688 60 mg BID BAY1128688 30 mg OD BAY1128688 30 mg twice daily (BID)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    2 / 10 (20.00%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Endometriosis ablation
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo BAY1128688 3 mg once daily (OD) BAY1128688 10 mg OD BAY1128688 60 mg BID BAY1128688 30 mg OD BAY1128688 30 mg twice daily (BID)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 31 (64.52%)
    5 / 11 (45.45%)
    10 / 31 (32.26%)
    21 / 27 (77.78%)
    8 / 10 (80.00%)
    6 / 11 (54.55%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Crying
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Swelling
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Breast pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    2 / 27 (7.41%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Endometriosis
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    4 / 27 (14.81%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    4
    1
    0
    4
    0
    0
    Metrorrhagia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Ovarian cyst
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Pelvic pain
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Premenstrual syndrome
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pelvic fluid collection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pneumonitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    Mood swings
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Panic attack
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Feeling guilty
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    2 / 10 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    2 / 27 (7.41%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Serum ferritin decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    2 / 27 (7.41%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    4 / 31 (12.90%)
    1 / 11 (9.09%)
    4 / 31 (12.90%)
    7 / 27 (25.93%)
    1 / 10 (10.00%)
    2 / 11 (18.18%)
         occurrences all number
    9
    1
    6
    7
    1
    3
    Migraine
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    1 / 31 (3.23%)
    2 / 27 (7.41%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    1
    3
    0
    0
    Eye disorders
    Episcleritis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 11 (9.09%)
    2 / 31 (6.45%)
    3 / 27 (11.11%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    2
    3
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    Hepatobiliary disorders
    Ocular icterus
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Solar urticaria
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Haematuria
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Polyuria
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    0 / 27 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    1 / 27 (3.70%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 31 (12.90%)
    0 / 11 (0.00%)
    1 / 31 (3.23%)
    2 / 27 (7.41%)
    2 / 10 (20.00%)
    1 / 11 (9.09%)
         occurrences all number
    4
    0
    1
    5
    2
    1
    Otitis externa
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 11 (9.09%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vulvovaginitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Myringitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 11 (0.00%)
    0 / 31 (0.00%)
    0 / 27 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Feb 2018
    All local amendments (1-8) were caused by the requests from the local regulatory authorities or ethics committees. Only one global amendment was submitted to Health Authorities. Amendment 9, dated 16 FEB 2018, was global. The protocol was amended mainly to implement the changes that had been made via local amendments, to ensure harmonization of study procedures. The following key modifications were made: Patients with copper IUDs could be included in the study, if IUD had been used for at least 6 months before study entry. Total sexual abstinence was added as an alternative method of contraception. Frequency of pregnancy testing was increased (with a maximum interval of 14 days). New exclusion criterion was introduced to exclude patients in custody.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Jul 2018
    Study BAY1128688/17472 (AKRENDO 1) was terminated early on 20 July 2018 due to hepatotoxicity
    -

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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