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    Clinical Trial Results:
    A randomized, parallel-group, double-blind and placebo-controlled, multicenter study to assess the efficacy and safety of vilaprisan in subjects with uterine fibroids

    Summary
    EudraCT number
    		 2016-003561-26
    Trial protocol
    		 CZ  
    Global end of trial date
    30 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jun 2022
    First version publication date
    09 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1002670/15790
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03400956
    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, ​+49 30 300139003, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary objective was to show superiority in treatment of heavy menstrual bleeding (HMB) of vilaprisan in subjects with uterine fibroids compared to placebo.
    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
    24 Jan 2018
    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
    United States: 40
    Country: Number of subjects enrolled
    Japan: 33
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    Russian Federation: 15
    Country: Number of subjects enrolled
    Ukraine: 3
    Worldwide total number of subjects
    96
    EEA total number of subjects
    5
    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)
    96
    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 87 study centers in USA, Japan, Czech Republic, Russia, and Ukraine between 24-Jan-2018 (first subject first visit) and 30-Jun-2021 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall, 481 subjects were screened, of them, 378 (78.6%) subjects were not randomized to treatment. The majority of these (n=286) were screen failures. Of the 103 subjects who were randomized, 91 subjects received study treatment. Full analysis set (FAS) included 96 subjects.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vilaprisan (A1)
    Arm description
    		 Vilaprisan in treatment period 1 for 12 weeks and in treatment period 2 for 12 weeks, separated by 1 bleeding episode.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilaprisan
    Investigational medicinal product code
    BAY1002670
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vilaprisan 2 mg in treatment period 1 for 12 weeks.

    Arm title
    		 Placebo+Vilaprisan (B1)
    Arm description
    		 Placebo in treatment period 1 for 12 weeks, and vilaprisan in treatment period 2 for 12 weeks, separated by 1 bleeding episode.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo in treatment period 1 for 12 weeks.

    Arm title
    		 Vilaprisan+Placebo (B2)
    Arm description
    		 Vilaprisan in treatment period 1 for 12 weeks, and placebo in treatment period 2 for 12 weeks, separated by 1 bleeding episode.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilaprisan
    Investigational medicinal product code
    BAY1002670
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vilaprisan 2 mg in treatment period 1 for 12 weeks.

    Number of subjects in period 1
    		Vilaprisan (A1) Placebo+Vilaprisan (B1) Vilaprisan+Placebo (B2)
    Started
    32
    33
    31
    Treated
    31
    30
    30
    Completed
    31
    26
    25
    Not completed
    1
    7
    6
         Consent withdrawn by subject
    -
    2
    3
         Adverse event, non-fatal
    -
    1
    -
         Unspecified
    1
    2
    2
         Lost to follow-up
    -
    -
    1
         Protocol deviation
    -
    2
    -
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vilaprisan (A1)
    Arm description
    		 Vilaprisan in treatment period 1 for 12 weeks and in treatment period 2 for 12 weeks, separated by 1 bleeding episode.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilaprisan
    Investigational medicinal product code
    BAY1002670
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vilaprisan 2 mg in treatment period 2 for 12 weeks, separated by 1 bleeding episode from treatment period 1.

    Arm title
    		 Placebo+Vilaprisan (B1)
    Arm description
    		 Placebo in treatment period 1 for 12 weeks, and vilaprisan in treatment period 2 for 12 weeks, separated by 1 bleeding episode.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilaprisan
    Investigational medicinal product code
    BAY1002670
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vilaprisan 2 mg in treatment period 2 for 12 weeks, separated by 1 bleeding episode from treatment period 1.

    Arm title
    		 Vilaprisan+Placebo (B2)
    Arm description
    		 Vilaprisan in treatment period 1 for 12 weeks, and placebo in treatment period 2 for 12 weeks, separated by 1 bleeding episode.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo in treatment period 2 for 12 weeks, separated by 1 bleeding episode from treatment period 1.

    Number of subjects in period 2 [1]
    		Vilaprisan (A1) Placebo+Vilaprisan (B1) Vilaprisan+Placebo (B2)
    Started
    9
    10
    9
    Completed
    5
    7
    5
    Not completed
    4
    3
    4
         Consent withdrawn by subject
    -
    -
    3
         Adverse event, non-fatal
    2
    1
    1
         Unspecified
    1
    1
    -
         Lost to follow-up
    1
    1
    -
    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: Not all the subjects completing the period 1 entered the period 2 due to early termination.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vilaprisan (A1)
    Reporting group description
    		 Vilaprisan in treatment period 1 for 12 weeks and in treatment period 2 for 12 weeks, separated by 1 bleeding episode.

    Reporting group title
    Placebo+Vilaprisan (B1)
    Reporting group description
    		 Placebo in treatment period 1 for 12 weeks, and vilaprisan in treatment period 2 for 12 weeks, separated by 1 bleeding episode.

    Reporting group title
    Vilaprisan+Placebo (B2)
    Reporting group description
    		 Vilaprisan in treatment period 1 for 12 weeks, and placebo in treatment period 2 for 12 weeks, separated by 1 bleeding episode.

    Reporting group values
    		 Vilaprisan (A1) Placebo+Vilaprisan (B1) Vilaprisan+Placebo (B2) Total
    Number of subjects
    		 32 33 31 96
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 43.1 ( 5.5 ) 42.7 ( 6.0 ) 43.8 ( 4.3 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 32 33 31 96
        Male
    		 0 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 11 11 11 33
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 6 7 8 21
        White
    		 13 15 10 38
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 2 0 2 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 3 5 10
        Not Hispanic or Latino
    		 30 30 26 86
        Unknown or Not Reported
    		 0 0 0 0
    Endometrial thickness
    Ultrasound examinations were performed. Endometrial thickness was measured in the medio-sagittal section as double-layer in millimeters. Baseline data of endometrial thickness is provided in below table.
    Units: Millimeters
        arithmetic mean (standard deviation)
    		 12.8 ( 4.5 ) 12.8 ( 2.9 ) 11.9 ( 3.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Vilaprisan (A1)
    Reporting group description
    		 Vilaprisan in treatment period 1 for 12 weeks and in treatment period 2 for 12 weeks, separated by 1 bleeding episode.

    Reporting group title
    Placebo+Vilaprisan (B1)
    Reporting group description
    		 Placebo in treatment period 1 for 12 weeks, and vilaprisan in treatment period 2 for 12 weeks, separated by 1 bleeding episode.

    Reporting group title
    Vilaprisan+Placebo (B2)
    Reporting group description
    		 Vilaprisan in treatment period 1 for 12 weeks, and placebo in treatment period 2 for 12 weeks, separated by 1 bleeding episode.
    Reporting group title
    Vilaprisan (A1)
    Reporting group description
    		 Vilaprisan in treatment period 1 for 12 weeks and in treatment period 2 for 12 weeks, separated by 1 bleeding episode.

    Reporting group title
    Placebo+Vilaprisan (B1)
    Reporting group description
    		 Placebo in treatment period 1 for 12 weeks, and vilaprisan in treatment period 2 for 12 weeks, separated by 1 bleeding episode.

    Reporting group title
    Vilaprisan+Placebo (B2)
    Reporting group description
    		 Vilaprisan in treatment period 1 for 12 weeks, and placebo in treatment period 2 for 12 weeks, separated by 1 bleeding episode.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS) consisted of all randomized subjects, excluding randomized subjects who did not start treatment period 1 (never received study drug) due to the study being closed prematurely (7 [6.8%]), and included 96 (93.2%) subjects.

    Primary: Number of subjects with amenorrhea

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    End point title
    		 Number of subjects with amenorrhea
    End point description
    Amenorrhea was defined as menstrual blood loss (MBL) < 2 mL during the last 28 days of treatment. The evaluation of MBL was based on the Alkaline hematin (AH) method.
    End point type
    Primary
    End point timeframe
    The last 28 days of treatment period 1
    End point values
    		 Vilaprisan (A1) Placebo+Vilaprisan (B1) Vilaprisan+Placebo (B2)
    Number of subjects analysed
    32
    33
    31
    Units: Subjects
    29
    1
    25
    Statistical analysis title
    		 Amenorrhea rates
    Statistical analysis description
    Vilaprisan (A1) and Vilaprisan+Placebo (B2) combined vs. Placebo+Vilaprisan (B1) in treatment period 1
    Comparison groups
    Vilaprisan (A1) v Placebo+Vilaprisan (B1) v Vilaprisan+Placebo (B2)
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 0.93
    Notes
    [1] - Number of subjects per treatment: 63 (Vilaprisan) / 33 (Placebo).

    Secondary: Number of subjects with heavy Menstrual Bleeding (HMB) response

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    End point title
    		 Number of subjects with heavy Menstrual Bleeding (HMB) response
    End point description
    HMB was defined as MBL <80.00 mL during the last 28 days of treatment and >50% reduction compared to baseline (assessed by the AH method).
    End point type
    Secondary
    End point timeframe
    The last 28 days of treatment period (TP) 1 and treatment period 2
    End point values
    		 Vilaprisan (A1) Placebo+Vilaprisan (B1) Vilaprisan+Placebo (B2)
    Number of subjects analysed
    32
    33
    31
    Units: Subjects
        Number of subjects analyzed in TP1
    32
    33
    31
        Treatment period 1
    30
    7
    26
        Number of subjects analysed in TP2
    8
    10
    8
        Treatment period 2
    6
    9
    1
    No statistical analyses for this end point

    Secondary: Time to onset of amenorrhea

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    End point title
    		 Time to onset of amenorrhea
    End point description
    Onset of amenorrhea was defined by the first day for which the MBL for all subsequent 28-day periods up to the end of a treatment period was <2 mL (amenorrhea defined similar to primary endpoint and assessed by the AH method). 99999 denotes value could not be calculated because less than 50% of subjects in group showed response.
    End point type
    Secondary
    End point timeframe
    In treatment period 1 (12 weeks) and in treatment period 2 (12 weeks)
    End point values
    		 Vilaprisan (A1) Placebo+Vilaprisan (B1) Vilaprisan+Placebo (B2)
    Number of subjects analysed
    32 [2]
    33 [3]
    31 [4]
    Units: Days
    median (inter-quartile range (Q1-Q3))
        Treatment period 1
    3 (2 to 4)
    99999 (99999 to 99999)
    3 (1 to 9)
        Treatment period 2
    3 (2 to 20)
    4 (3 to 99999)
    99999 (99999 to 99999)
    Notes
    [2] - TP 1: 32 TP 2: 8
    [3] - TP 1: 33 TP 2: 10
    [4] - TP 1: 31 TP 2: 8
    No statistical analyses for this end point

    Secondary: Time to onset of controlled bleeding

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    End point title
    		 Time to onset of controlled bleeding
    End point description
    Onset of controlled bleeding was defined by the first day for which the MBL for all subsequent 28-day periods up to the end of a treatment period was <80.00 mL (assessed by the AH method). 99999 denotes value could not be calculated because less than 50% of subjects in group showed response.
    End point type
    Secondary
    End point timeframe
    In treatment period 1 (12 weeks) and in treatment period 2 (12 weeks)
    End point values
    		 Vilaprisan (A1) Placebo+Vilaprisan (B1) Vilaprisan+Placebo (B2)
    Number of subjects analysed
    32 [5]
    33 [6]
    31 [7]
    Units: Days
    median (inter-quartile range (Q1-Q3))
        Treatment period 1
    1 (1 to 1)
    99999 (99999 to 99999)
    1 (1 to 2)
        Treatment period 2
    1.5 (1 to 1.9)
    1 (1 to 2)
    99999 (99999 to 99999)
    Notes
    [5] - TP 1: 32 TP 2: 8
    [6] - TP 1: 33 TP 2: 10
    [7] - TP 1: 31 TP 2: 8
    No statistical analyses for this end point

    Secondary: Number of subjects with absence of bleeding (spotting allowed)

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    End point title
    		 Number of subjects with absence of bleeding (spotting allowed)
    End point description
    Absence of bleeding was defined as no scheduled or unscheduled bleeding (spotting allowed) during the last 28 days of a treatment period based on subjects’ daily responses to the UF-DBD (Uterine Fibroid Daily Bleeding Diary).
    End point type
    Secondary
    End point timeframe
    The last 28 days of treatment period 1 and treatment period 2
    End point values
    		 Vilaprisan (A1) Placebo+Vilaprisan (B1) Vilaprisan+Placebo (B2)
    Number of subjects analysed
    32
    33
    31
    Units: Subjects
        Number of subjects analysed in TP1
    32
    33
    31
        Treatment period 1
    29
    2
    25
        Number of subjects analysed in TP2
    8
    10
    8
        Treatment period 2
    6
    8
    1
    No statistical analyses for this end point

    Secondary: Number of subjects by endometrial biopsy main results (majority read, main diagnosis)

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    End point title
    		 Number of subjects by endometrial biopsy main results (majority read, main diagnosis)
    End point description
    Number of subjects with endometrial histology findings, e.g. benign endometrium, Malignant Neoplasm, Hyperplasia 2014, no atypia or Hyperplasia 2014, atypia and Endometrial Polyps.
    End point type
    Secondary
    End point timeframe
    Up to 36 weeks
    End point values
    		 Vilaprisan (A1) Placebo+Vilaprisan (B1) Vilaprisan+Placebo (B2)
    Number of subjects analysed
    31
    30
    30
    Units: Subjects
        Adequate endometrial tissue
    31
    30
    26
        Benign Endometrium
    31
    30
    26
        Hyperplasia WHO 2014, no atypia
    0
    0
    0
        Hyperplasia WHO 2014, atypia
    0
    0
    0
        Malignant Neoplasm
    0
    0
    0
        Endometrial Polyps
    2
    0
    1
    No statistical analyses for this end point

    Secondary: Change from baseline of endometrial thickness

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    End point title
    		 Change from baseline of endometrial thickness
    End point description
    Ultrasound examinations were performed. Endometrial thickness was measured in the medio-sagittal section as double-layer in millimeters. Summary statistics for change from baseline in endometrial thickness was provided in below table.
    End point type
    Secondary
    End point timeframe
    In treatment period 1 (12 weeks) and in treatment period 2 (12 weeks)
    End point values
    		 Vilaprisan (A1) Placebo+Vilaprisan (B1) Vilaprisan+Placebo (B2)
    Number of subjects analysed
    31 [8]
    30 [9]
    30 [10]
    Units: Millimeters
    arithmetic mean (standard deviation)
        Treatment period (TP) 1
    -2.5 ( 4.1 )
    -2.8 ( 2.6 )
    -3.1 ( 3.7 )
        Treatment period 2
    -5.3 ( 7.6 )
    -3.5 ( 4.1 )
    -0.4 ( 4.1 )
    Notes
    [8] - TP 1: 30 TP 2: 7
    [9] - TP 1: 30 TP 2: 10
    [10] - TP 1: 29 TP 2: 7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The observation period for AEs started with signing the informed consent and ended with the last visit.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Vilaprisan (A1) - Treatment emergent AEs
    Reporting group description
    		 Vilaprisan in treatment period 1 for 12 weeks and in treatment period 2 for 12 weeks, separated by 1 bleeding episode. TEAEs: defined as AEs that "started from the first application of study medication up to 60 calendar days after end of treatment with study medication".

    Reporting group title
    Placebo+Vilaprisan (B1) - Treatment emergent AEs
    Reporting group description
    		 Placebo in treatment period 1 for 12 weeks, and vilaprisan in treatment period 2 for 12 weeks, separated by 1 bleeding episode. TEAEs: defined as AEs that "started from the first application of study medication up to 60 calendar days after end of treatment with study medication".

    Reporting group title
    Vilaprisan +Placebo (B2) - Treatment emergent AEs
    Reporting group description
    		 Vilaprisan in treatment period 1 for 12 weeks, and placebo in treatment period 2 for 12 weeks, separated by 1 bleeding episode. TEAEs: defined as AEs that "started from the first application of study medication up to 60 calendar days after end of treatment with study medication".

    Reporting group title
    Vilaprisan (A1) - Post treatment AEs
    Reporting group description
    		 Vilaprisan in treatment period 1 for 12 weeks and in treatment period 2 for 12 weeks, separated by 1 bleeding episode. Post-treatment AEs: defined as all AEs that started from Day 61 after the end of treatment with study medication. (All AEs identified during the safety follow-up are included in this portion).

    Reporting group title
    Placebo+Vilaprisan (B1) - Post treatment AEs
    Reporting group description
    		 Placebo in treatment period 1 for 12 weeks, and vilaprisan in treatment period 2 for 12 weeks, separated by 1 bleeding episode. Post-treatment AEs: defined as all AEs that started from Day 61 after the end of treatment with study medication. (All AEs identified during the safety follow-up are included in this portion).

    Reporting group title
    Vilaprisan+Placebo (B2) - Post treatment AEs
    Reporting group description
    		 Vilaprisan in treatment period 1 for 12 weeks, and placebo in treatment period 2 for 12 weeks, separated by 1 bleeding episode. Post-treatment AEs: defined as all AEs that started from Day 61 after the end of treatment with study medication. (All AEs identified during the safety follow-up are included in this portion).

    Serious adverse events
    		 Vilaprisan (A1) - Treatment emergent AEs Placebo+Vilaprisan (B1) - Treatment emergent AEs Vilaprisan +Placebo (B2) - Treatment emergent AEs Vilaprisan (A1) - Post treatment AEs Placebo+Vilaprisan (B1) - Post treatment AEs Vilaprisan+Placebo (B2) - Post treatment AEs
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 31 (3.23%)
    4 / 30 (13.33%)
    0 / 30 (0.00%)
    7 / 31 (22.58%)
    8 / 30 (26.67%)
    3 / 30 (10.00%)
         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
    Liver function test increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial neoplasm
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenal adenoma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (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
    Bile duct cancer
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hysterectomy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    3 / 30 (10.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myomectomy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingectomy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (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
    Hysterosalpingo-oophorectomy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 30 (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
    Urinary cystectomy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (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
    Hysterosalpingectomy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine dilation and curettage
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis ablation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (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
    Uterine leiomyoma embolisation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Reproductive system and breast disorders
    Heavy menstrual bleeding
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    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
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal mass
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Tendonitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (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
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vilaprisan (A1) - Treatment emergent AEs Placebo+Vilaprisan (B1) - Treatment emergent AEs Vilaprisan +Placebo (B2) - Treatment emergent AEs Vilaprisan (A1) - Post treatment AEs Placebo+Vilaprisan (B1) - Post treatment AEs Vilaprisan+Placebo (B2) - Post treatment AEs
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 31 (58.06%)
    19 / 30 (63.33%)
    16 / 30 (53.33%)
    10 / 31 (32.26%)
    12 / 30 (40.00%)
    12 / 30 (40.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    4 / 31 (12.90%)
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    4
    2
    1
    1
    0
    3
    Hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    1
    2
    1
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 31 (3.23%)
    4 / 30 (13.33%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    5
    0
    0
    2
    0
    Premenstrual syndrome
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 30 (10.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    3
    0
    0
    0
    1
    Uterine haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Endometrial thickening
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    0
    0
    0
    0
    1
    Genital haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    Intermenstrual bleeding
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    0
    2
    2
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 31 (12.90%)
    1 / 30 (3.33%)
    4 / 30 (13.33%)
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    6
    1
    4
    1
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    1
    2
    0
    2
    3
    1
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    3 / 30 (10.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    0
    0
    3
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    Nausea
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    1
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    3 / 30 (10.00%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    2
    0
    1
    1
    2
    3
    Infections and infestations
    Bacterial vaginosis
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    0
    0
    2
    0
    Influenza
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    0
    1
    1
    0
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 31 (9.68%)
    3 / 30 (10.00%)
    4 / 30 (13.33%)
    5 / 31 (16.13%)
    1 / 30 (3.33%)
    5 / 30 (16.67%)
         occurrences all number
    3
    3
    4
    9
    1
    5
    Vulvovaginal mycotic infection
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 30 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    4 / 30 (13.33%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    0
    2
    4
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Nov 2017
    The collection period for sanitary products was extended to cover the whole treatment period.
    04 Jul 2018
    1) Text added describing hepatic safety signal with Esmya (ulipristal acetate), a compound that belongs to the compound group of selective PRMs, and the result of the respective PRAC review procedure including risk minimization measures. 2) Provided rationale that vilaprisan is structurally different from other selective PRMs. 3) Description of increased frequency of liver monitoring and its background in subsection “safety monitoring” added. The criterion about abnormal liver parameters was revised. The diagnosis of chronic hepatitis B / C infection was added to exclusion criteria. A description for liver symptom inquiry was included and added to all visits. More detailed instructions for the monitoring of liver parameters and liver disorders and for close observation in cases with increased liver parameters and liver disorders were added.
    11 Dec 2018
    Introduction of measures for the temporary pause of the study: due to preliminary findings from 2-year animal carcinogenicity studies, the sponsor decided on 3-Dec-2018 that patients must not start treatment/not start a new treatment course while the preliminary findings from the carcinogenicity studies and their relevance to humans were further investigated.
    20 Nov 2019
    1) Introduction of measures and processes to prepare the study for an orderly closure to allow for thorough evaluation of preclinical and clinical data prior to further decisions on the development of vilaprisan. 2) Information on carcinogenicity studies with vilaprisan in rodents as well as details regarding the additional safety measures were added, including adrenal monitoring, endometrial monitoring and skin monitoring. 3) Primary efficacy analysis limited to Treatment Period 1.
    17 Feb 2020
    1) The amendment addresses comments from the FDA regarding details of the safety-follow-up measures introduced in protocol amendment 5, Version 5.0. 2) Described how subjects were counseled when test results (e.g., hormone, liver, physical examination) were abnormal but still below the thresholds to trigger outside evaluation in the context of the study. In such cases subjects were at least to be counseled about medical follow up according to local practice. 3) Revised the interval for blood sampling after intake of high doses of biotin from 8 to 72 hours. 4) Added glycosylated hemoglobin (HbA1c) to the parameters measured for adrenal monitoring also in subjects who had completed or discontinued the study before or during the temporary pause. 5) Added clarification that all randomized subjects belong to the FAS, excluding randomized subjects who did not start Treatment Period 1 due to the premature closure of the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    03 Dec 2018
    Bayer decided to temporarily pause enrollment and randomization, and to temporarily stop study treatment in already randomized patients after completion of the ongoing treatment period.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    - The trial was terminated earlier than planned. It was sufficiently advanced to allow for meaningful analysis. - In many subjects, follow up phase was longer than the planned one. - Safety evaluations were not limited to the planned timepoints.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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