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    Clinical Trial Results:
    A randomized, parallel-group, double-blind, placebo-controlled, multi-center study to assess the efficacy and safety of different doses of BAY 1002670 in subjects with uterine fibroids over 3 months

    Summary
    EudraCT number
    		 2013-003945-40
    Trial protocol
    		 SE   FI   NO   HU   CZ   BE   ES   BG  
    Global end of trial date
    04 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 May 2017
    First version publication date
    19 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY1002670/15788
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02131662
    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
    04 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the dose-response relationship of vilaprisan (VPR) in subjects with uterine fibroids.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 May 2014
    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
    Spain: 30
    Country: Number of subjects enrolled
    Sweden: 38
    Country: Number of subjects enrolled
    United States: 306
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Bulgaria: 44
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    Czech Republic: 40
    Country: Number of subjects enrolled
    Finland: 47
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    Japan: 98
    Country: Number of subjects enrolled
    Norway: 34
    Worldwide total number of subjects
    748
    EEA total number of subjects
    317
    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)
    748
    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 multiple centers in 12 countries worldwide between 15 May 2014 (first subject first visit) and 04 May 2016 (last subject last visit).

    Pre-assignment
    Screening details
    		 748 subjects were enrolled; 439 subjects were not randomized, the majority was screen failures. Therefore, 309 subjects were randomized. 9 randomized subjects were not treated. 14 subjects prematurely discontinued study treatment. Overall, 93% of randomized subjects completed the treatment period; 79% of subjects completed the follow-up period.

    Period 1
    Period 1 title
    Overall study (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
    		 VPR 4 mg
    Arm description
    		 Subjects received 4 milligram (mg) VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilaprisan Film-coated tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received treatment with VPR 4 mg, one tablet taken orally daily about the same time every day. Treatment started during the first week of the menstrual cycle following randomization. The treatment period was 12 weeks (84 days).

    Arm title
    		 VPR 2 mg
    Arm description
    		 Subjects received 2 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilaprisan Film-coated tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received treatment with VPR 2 mg, one tablet taken orally daily about the same time every day. Treatment started during the first week of the menstrual cycle following randomization. The treatment period was 12 weeks (84 days).

    Arm title
    		 VPR 1 mg
    Arm description
    		 Subjects received 1 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilaprisan Film-coated tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received treatment with either VPR (0.5 mg, 1 mg, 2 mg, or 4 mg) or matching placebo, one tablet taken orally daily about the same time every day. Treatment started during the first week of the menstrual cycle following randomization. The treatment period was 12 weeks (84 days).

    Investigational medicinal product name
    Vilaprisan Film-coated tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received treatment with VPR 1 mg, one tablet taken orally daily about the same time every day. Treatment started during the first week of the menstrual cycle following randomization. The treatment period was 12 weeks (84 days).

    Arm title
    		 VPR 0.5 mg
    Arm description
    		 Subjects received 0.5 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vilaprisan Film-coated tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received treatment with VPR 0.5 mg, one tablet taken orally daily about the same time every day. Treatment started during the first week of the menstrual cycle following randomization. The treatment period was 12 weeks (84 days).

    Arm title
    		 Placebo
    Arm description
    		 Subjects received matching placebo tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching placebo tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received treatment with matching placebo, one tablet taken orally daily about the same time every day. Treatment started during the first week of the menstrual cycle following randomization. The treatment period was 12 weeks (84 days).

    Number of subjects in period 1 [1]
    		VPR 4 mg VPR 2 mg VPR 1 mg VPR 0.5 mg Placebo
    Started
    60
    61
    61
    60
    58
    Treated
    60
    61
    61
    60
    58
    Completed treatment
    57
    60
    61
    56
    52
    Completed follow-up
    54
    47
    56
    42
    44
    Completed
    54
    47
    56
    41
    43
    Not completed
    6
    14
    5
    19
    15
         Wish for pregnancy
    -
    -
    -
    -
    1
         Other
    2
    4
    3
    3
    4
         Pregnancy
    -
    1
    -
    1
    -
         Adverse event
    -
    1
    1
    1
    3
         Lost to follow-up
    1
    3
    -
    9
    -
         Protocol deviation
    1
    -
    -
    -
    -
         Withdrawal by subject
    1
    5
    1
    5
    6
         Lack of efficacy
    1
    -
    -
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all enrolled subjects received treatment. Only treated subjects were included in the baseline period. There were 2 subjects (1 subject in VPR 0.5 mg group and 1 subject in placebo group) who did not complete treatment period but completed follow-up period according to protocol. These 2 subjects were considered not completed for overall study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    VPR 4 mg
    Reporting group description
    		 Subjects received 4 milligram (mg) VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    VPR 2 mg
    Reporting group description
    		 Subjects received 2 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    VPR 1 mg
    Reporting group description
    		 Subjects received 1 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    VPR 0.5 mg
    Reporting group description
    		 Subjects received 0.5 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group values
    		 VPR 4 mg VPR 2 mg VPR 1 mg VPR 0.5 mg Placebo Total
    Number of subjects
    		 60 61 61 60 58 300
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.5 ( 4.2 ) 43 ( 4.6 ) 41.9 ( 4.5 ) 41.7 ( 4.9 ) 42.8 ( 5.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 60 61 61 60 58 300
        Male
    		 0 0 0 0 0 0
    Baseline menstrual blood loss by MP
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    		 172.3 ( 111.86 ) 176.9 ( 128.71 ) 178.2 ( 116.64 ) 173.6 ( 94.62 ) 164.6 ( 78.71 ) -
    Volume of largest fibroid by US
    Units: millilitre(s)
        arithmetic mean (standard deviation)
    		 78.92 ( 95.644 ) 77.66 ( 91.605 ) 74.55 ( 88.397 ) 81.69 ( 85.62 ) 99.03 ( 117.379 ) -

    End points

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    End points reporting groups
    Reporting group title
    VPR 4 mg
    Reporting group description
    		 Subjects received 4 milligram (mg) VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    VPR 2 mg
    Reporting group description
    		 Subjects received 2 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    VPR 1 mg
    Reporting group description
    		 Subjects received 1 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    VPR 0.5 mg
    Reporting group description
    		 Subjects received 0.5 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS (N=300) included all subjects who took at least 1 dose of study drug.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF (N= 300) included all subjects who took at least 1 dose of study drug.

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS (N=221) included all subjects in the FAS without any major protocol deviation.

    Subject analysis set title
    Method interchange analysis set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Method interchange analysis set (N=399) for the assessment of the interchangeability of the menstrual pictogram (MP) and the alkaline hematin (AH) method to judge menstrual blood loss (MBL) included subjects with sanitary product data for which there was a matching pair of MP score and AH value available.

    Primary: Percentage of subjects with amenorrhea, defined as no scheduled or unscheduled bleeding/spotting after the end of the initial bleeding episode until end of treatment

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    End point title
    		 Percentage of subjects with amenorrhea, defined as no scheduled or unscheduled bleeding/spotting after the end of the initial bleeding episode until end of treatment
    End point description
    Amenorrhea was defined as no scheduled or unscheduled bleeding/spotting after the end of the initial bleeding episode until end of treatment. Dose-response curve was estimated based on the primary endpoint. The 4 parameters characterizing the dose-response curve were reported in other pre-specifided endpoints below.
    End point type
    Primary
    End point timeframe
    After end of the initial bleeding episode until the end of treatment
    End point values
    		 VPR 4 mg VPR 2 mg VPR 1 mg VPR 0.5 mg Placebo
    Number of subjects analysed
    60
    61
    61
    60
    58
    Units: Percentage
        number (not applicable)
    60
    54.1
    55.7
    30
    1.7
    Statistical analysis title
    		 Placebo-adjusted amenorrhea rate of VPR 4 mg
    Statistical analysis description
    The placebo-adjusted amenorrhea rate was summarized by dose with unconditional 2-sided 95% confidence intervals for each active treatment group. This unconditional confidence interval was calculated by inverting 2 separate one-sided tests of half the nominal significance level each.
    Comparison groups
    VPR 4 mg v Placebo
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Proportion difference
    Point estimate
    58.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 44.55
         upper limit
    		 70.94
    Statistical analysis title
    		 Placebo-adjusted amenorrhea rate of VPR 2 mg
    Statistical analysis description
    The placebo-adjusted amenorrhea rate was summarized by dose with unconditional 2-sided 95% confidence intervals for each active treatment group. This unconditional confidence interval was calculated by inverting 2 separate one-sided tests of half the nominal significance level each.
    Comparison groups
    VPR 2 mg v Placebo
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Proportion difference
    Point estimate
    52.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 38.8
         upper limit
    		 65.42
    Statistical analysis title
    		 Placebo-adjusted amenorrhea rate of VPR 1 mg
    Statistical analysis description
    The placebo-adjusted amenorrhea rate was summarized by dose with unconditional 2-sided 95% confidence intervals for each active treatment group. This unconditional confidence interval was calculated by inverting 2 separate one-sided tests of half the nominal significance level each.
    Comparison groups
    VPR 1 mg v Placebo
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Proportion difference
    Point estimate
    54.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 40.41
         upper limit
    		 66.95
    Statistical analysis title
    		 Placebo-adjusted amenorrhea rate of VPR 0.5 mg
    Statistical analysis description
    The placebo-adjusted amenorrhea rate was summarized by dose with unconditional 2-sided 95% confidence intervals for each active treatment group. This unconditional confidence interval was calculated by inverting 2 separate one-sided tests of half the nominal significance level each.
    Comparison groups
    VPR 0.5 mg v Placebo
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Proportion difference
    Point estimate
    28.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.92
         upper limit
    		 41.5

    Secondary: Change in volume of menstrual blood loss per 28 days from baseline during treatment by reference period (assessed by Alkaline Hematin method)

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    End point title
    		 Change in volume of menstrual blood loss per 28 days from baseline during treatment by reference period (assessed by Alkaline Hematin method)
    End point description
    In the below table, "N" signifies subjects who were evaluable for the specific parameter at that timepoint for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    From baseline to end of follow-up
    End point values
    		 VPR 4 mg VPR 2 mg VPR 1 mg VPR 0.5 mg Placebo
    Number of subjects analysed
    60
    61
    61
    60
    58
    Units: mL
    arithmetic mean (standard deviation)
        1st period (N=46, 46, 47, 45, 45)
    -79.83 ( 234.22 )
    -30.18 ( 106.82 )
    -55.42 ( 109.29 )
    -44.14 ( 110.61 )
    17.22 ( 124.14 )
        2ndperiod (N=44, 45, 47, 44, 44)
    -203.43 ( 215.23 )
    -166.71 ( 149.57 )
    -181.76 ( 111.98 )
    -146.32 ( 136.97 )
    -28.42 ( 113.93 )
        3rd period (N=43, 45, 47, 43, 40)
    -205.08 ( 214.8 )
    -173.38 ( 153.37 )
    -185.77 ( 106.91 )
    -147.55 ( 138.4 )
    -36.69 ( 117.98 )
    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 (assessed by MP, Version 2014) for all subsequent 28-day periods up to the end of the treatment period was less than 80 mL. Kaplan-Meier estimated time to onset of controlled bleeding (days) was reported. Number of bleeding events was 59, 61, 59, 53, 26 for VPR 4 mg, VPR 2 mg, VPR 1 mg, VPR 0.5 mg and placebo respectively. '99999' indicates that the data were not appilcable for that specific reporting group.
    End point type
    Secondary
    End point timeframe
    During treatment period
    End point values
    		 VPR 4 mg VPR 2 mg VPR 1 mg VPR 0.5 mg Placebo
    Number of subjects analysed
    60
    61
    59 [1]
    53 [2]
    26 [3]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    2 (1 to 3)
    2 (1 to 3)
    3 (1 to 3)
    2 (1 to 4)
    99999 (32 to 99999)
    Notes
    [1] - Only subjects with valid data for this assessment were included
    [2] - Only subjects with valid data for this assessment were included
    [3] - Only subjects with valid data for this assessment were included
    No statistical analyses for this end point

    Secondary: Percent change in volume of largest fibroid compared to baseline measured by MRI

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    End point title
    		 Percent change in volume of largest fibroid compared to baseline measured by MRI
    End point description
    Pelvic Magnetic resonance imagings (MRI), without contrast agents, were performed for volume measurements of the uterus and fibroids preferably using 1.5 Tesla scanners or higher. Images were sent to the imaging core laboratory for evaluation. Volume measurements of the uterus and fibroids were performed centrally by independent radiologist(s).
    End point type
    Secondary
    End point timeframe
    From baseline to end of follow-up period
    End point values
    		 VPR 4 mg VPR 2 mg VPR 1 mg VPR 0.5 mg Placebo
    Number of subjects analysed
    60
    61
    61
    60
    58
    Units: mL
    median (full range (min-max))
        End of treatment (N=47, 52, 58, 47, 48)
    -41.4 (-98 to 10)
    -27.2 (-81 to 47)
    -18.9 (-85 to 11314)
    -14.9 (-68 to 74)
    4.9 (-67 to 271)
        Follow-up (N=45, 48, 55, 40, 41)
    -26.9 (-94 to 18)
    -15 (-82 to 52)
    -9.7 (-79 to 437)
    -9.3 (-96 to 91)
    5.1 (-59 to 364)
    No statistical analyses for this end point

    Other pre-specified: Exposure-response analysis of Vilaprisan - number of subjects achieving maximum effect (Emax) of induced amenorrhea

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    End point title
    		 Exposure-response analysis of Vilaprisan - number of subjects achieving maximum effect (Emax) of induced amenorrhea
    End point description
    Maximum effect of vilaprisan on induced amenorrhea during treatment period. Induced amenorrhea was defined as number of subjects with amenorrhea (that is, all days with bleeding intensity 1 = none) , i.e. no bleeding or spotting allowed after initial bleeding episode until end of treatment.
    End point type
    Other pre-specified
    End point timeframe
    From start of the study treatment to Day 84 (treatment period)
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    267 [4]
    Units: Percentage of subjects
        number (confidence interval 95%)
    59 (49 to 68)
    Notes
    [4] - Only subjects with valid data for this assessment were included.
    No statistical analyses for this end point

    Other pre-specified: Steady-state exposure achieving half-maximal effect (EAUC50) of induced amenorrhea during treatment period of Vilaprisan

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    End point title
    		 Steady-state exposure achieving half-maximal effect (EAUC50) of induced amenorrhea during treatment period of Vilaprisan
    End point description
    Area-under-the-curve (AUC) of vilaprisan between 0 and 24 hours post-dose at steady-state achieving 50% of maximum effect of vilaprisan on induced amenorrhea during treatment period. Induced amenorrhea was defined as number of subjects with induced-amenorrhea (that is, all days with bleeding intensity 1 = none) , i.e. no bleeding or spotting allowed after initial bleeding episode until end of treatment.
    End point type
    Other pre-specified
    End point timeframe
    From start of the study treatment to Day 84 (treatment period)
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    267 [5]
    Units: mcg*h/L
        number (confidence interval 95%)
    36.93 (27.69 to 48.69)
    Notes
    [5] - Only subjects with valid data for this assessment were included.
    No statistical analyses for this end point

    Other pre-specified: Exposure-response analysis of Vilaprisan - Predicted fraction of subjects below 90% of the maximum probability of induced amenorrhea

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    End point title
    		 Exposure-response analysis of Vilaprisan - Predicted fraction of subjects below 90% of the maximum probability of induced amenorrhea
    End point description
    Exposure-response model predicted fraction of subjects below 90% of the maximum probability of induced amenorrhea (that is, all days with bleeding intensity 1 = none) , i.e. no bleeding or spotting allowed after initial bleeding episode until end of treatment.
    End point type
    Other pre-specified
    End point timeframe
    From start of the study treatment to Day 84 (treatment period)
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    267 [6]
    Units: Percentage of subjects
    number (not applicable)
        1 mg
    36
        2 mg
    2
        3 mg
    1
    Notes
    [6] - Only subjects with valid data for this assessment were included.
    No statistical analyses for this end point

    Other pre-specified: Assement of interchangeability of MP and AH method

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    End point title
    		 Assement of interchangeability of MP and AH method
    End point description
    Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of MP method for detecting heavy menstrual bleeding at baseline were calculated against the AH method.
    End point type
    Other pre-specified
    End point timeframe
    From baseline to treatment period
    End point values
    		 Method interchange analysis set
    Number of subjects analysed
    399
    Units: Percentage
    number (not applicable)
        Version 2014: Sensitivity
    83.3
        Version 2014: Specificity
    77.3
        Version 2014: PPV
    82.1
        Version 2014: NPV
    78.7
        Version 2016: Sensitivity
    89.7
        Version 2016: Specificity
    54.5
        Version 2016: PPV
    70.6
        Version 2016: NPV
    81.4
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects with Amenorrhea (defined as MBL < 2 mL) during the last 28 days of treatment

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    End point title
    		 Percentage of subjects with Amenorrhea (defined as MBL < 2 mL) during the last 28 days of treatment
    End point description
    End point type
    Other pre-specified
    End point timeframe
    After end of the initial bleeding episode until the end of treatment
    End point values
    		 VPR 4 mg VPR 2 mg VPR 1 mg VPR 0.5 mg Placebo
    Number of subjects analysed
    60
    61
    61
    60
    58
    Units: Percentage of subjects
        number (not applicable)
    83.33
    88.52
    85.25
    65
    8.62
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects with HMB response during the last 28 days of treatment

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    End point title
    		 Percentage of subjects with HMB response during the last 28 days of treatment
    End point description
    End point type
    Other pre-specified
    End point timeframe
    After end of the initial bleeding episode until the end of treatment
    End point values
    		 VPR 4 mg VPR 2 mg VPR 1 mg VPR 0.5 mg Placebo
    Number of subjects analysed
    60
    61
    61
    60
    58
    Units: Percentage of subjects
        number (not applicable)
    93.33
    96.72
    93.44
    81.67
    29.31
    No statistical analyses for this end point

    Other pre-specified: Estimated dose-response curve based on amenorrhea - E0 and Emax

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    End point title
    		 Estimated dose-response curve based on amenorrhea - E0 and Emax
    End point description
    The primary objective was to estimate the dose-response curve based on the primary endpoint: subjects with amenorrhea. The number of subjects with amenorrhea was assumed to be binomial distributed. A 4 parameters logistic model was used to fit the observed data for characterizing the dose-response curve: E0, Emax, ED50 and δ. The model is defined as p(d)=E0 + Emax/{1+ e^[{ED50-d)/δ]}. E0 is the amenorrhea rate for placebo; Emax is the maximum effect attributable to the drug (compared with the basal effect with dose at d=0 [placebo group], the maximum increase of drug effect).
    End point type
    Other pre-specified
    End point timeframe
    After end of the initial bleeding episode until the end of treatment
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    300
    Units: Percentage
    number (not applicable)
        E0
    0.0082
        Emax
    0.57
    No statistical analyses for this end point

    Other pre-specified: Estimated dose-response curve based on amenorrhea - ED50

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    End point title
    		 Estimated dose-response curve based on amenorrhea - ED50
    End point description
    ED50 is the dose at which 50% of Emax were achieved.
    End point type
    Other pre-specified
    End point timeframe
    After end of the initial bleeding episode until the end of treatment
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    300
    Units: mg
        number (not applicable)
    0.5
    No statistical analyses for this end point

    Other pre-specified: Estimated dose-response curve based on amenorrhea - δ

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    End point title
    		 Estimated dose-response curve based on amenorrhea - δ
    End point description
    δ is hill slope parameter for characterizing the dose-response curve.
    End point type
    Other pre-specified
    End point timeframe
    After end of the initial bleeding episode until the end of treatment
    End point values
    		 Full Analysis Set
    Number of subjects analysed
    300
    Units: not applicable
        number (not applicable)
    0.145
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment until the end of the 6-month follow-up period
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    VPR 4 mg
    Reporting group description
    		 Subjects received 4 milligram (mg) VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    VPR 2 mg
    Reporting group description
    		 Subjects received 2 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    VPR 1 mg
    Reporting group description
    		 Subjects received 1 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    VPR 0.5 mg
    Reporting group description
    		 Subjects received 0.5 mg VPR tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects matching placebo tablet once daily orally for 12 weeks (84 days) from the first week of the menstrual cycle following randomization.

    Serious adverse events
    		 VPR 4 mg VPR 2 mg VPR 1 mg VPR 0.5 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 61 (6.56%)
    3 / 61 (4.92%)
    2 / 60 (3.33%)
    2 / 58 (3.45%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    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
    Metastases to ovary
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    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
    Uterine leiomyoma
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    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
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous complete
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 61 (0.00%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    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
    Pulmonary embolism
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 VPR 4 mg VPR 2 mg VPR 1 mg VPR 0.5 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 60 (51.67%)
    30 / 61 (49.18%)
    31 / 61 (50.82%)
    32 / 60 (53.33%)
    32 / 58 (55.17%)
    Investigations
    Weight increased
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 61 (1.64%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    4
    1
    1
    0
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    8 / 60 (13.33%)
    5 / 61 (8.20%)
    5 / 61 (8.20%)
    6 / 60 (10.00%)
    4 / 58 (6.90%)
         occurrences all number
    8
    5
    6
    8
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 61 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    5
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    5 / 60 (8.33%)
    5 / 61 (8.20%)
    7 / 61 (11.48%)
    5 / 60 (8.33%)
    7 / 58 (12.07%)
         occurrences all number
    8
    6
    13
    9
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 61 (4.92%)
    3 / 61 (4.92%)
    2 / 60 (3.33%)
    5 / 58 (8.62%)
         occurrences all number
    3
    3
    4
    2
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 61 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    9
    0
    1
    0
    3
    Nausea
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 61 (4.92%)
    0 / 61 (0.00%)
    2 / 60 (3.33%)
    0 / 58 (0.00%)
         occurrences all number
    4
    3
    0
    2
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 61 (3.28%)
    1 / 61 (1.64%)
    4 / 60 (6.67%)
    1 / 58 (1.72%)
         occurrences all number
    2
    2
    1
    5
    1
    Menorrhagia
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 61 (6.56%)
    6 / 61 (9.84%)
    3 / 60 (5.00%)
    4 / 58 (6.90%)
         occurrences all number
    3
    6
    6
    4
    6
    Metrorrhagia
         subjects affected / exposed
    5 / 60 (8.33%)
    7 / 61 (11.48%)
    7 / 61 (11.48%)
    4 / 60 (6.67%)
    1 / 58 (1.72%)
         occurrences all number
    7
    17
    10
    5
    1
    Ovarian cyst
         subjects affected / exposed
    4 / 60 (6.67%)
    5 / 61 (8.20%)
    4 / 61 (6.56%)
    15 / 60 (25.00%)
    5 / 58 (8.62%)
         occurrences all number
    5
    5
    6
    16
    7
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 61 (1.64%)
    2 / 61 (3.28%)
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences all number
    3
    1
    4
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 61 (0.00%)
    0 / 61 (0.00%)
    0 / 60 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 60 (6.67%)
    4 / 61 (6.56%)
    0 / 61 (0.00%)
    2 / 60 (3.33%)
    2 / 58 (3.45%)
         occurrences all number
    6
    4
    0
    2
    2
    Infections and infestations
    Bacterial vaginosis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    1 / 61 (1.64%)
    3 / 60 (5.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    1
    2
    3
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 61 (1.64%)
    2 / 61 (3.28%)
    4 / 60 (6.67%)
    7 / 58 (12.07%)
         occurrences all number
    5
    1
    2
    4
    7
    Urinary tract infection
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 61 (0.00%)
    1 / 61 (1.64%)
    0 / 60 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    3
    0
    1
    0
    3
    Vulvovaginal mycotic infection
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 61 (1.64%)
    4 / 61 (6.56%)
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    3
    1
    4
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Apr 2014
    Following advice from FDA, the changes below were made. - Stratification of the treatment groups by baseline hemoglobin level was added. - A requirement for an immediate unscheduled endometrial biopsy was added in the event of endometrial thickness (double layer) > 18 mm or a suspicious bleeding pattern was detected. Prior to this, subjects were to be followed, and an unscheduled biopsy was to be conducted after 1 month if not resolved. - The requirement of using a non-hormonal barrier method of contraception during the study was changed to a double-barrier method. * Rationale was added explaining the expectation that 17% of subjects would be excluded from the PPS.. - The WHO confirmed the international nonproprietary name “vilaprisan” for BAY 1002670, which was implemented. The WHO confirmed the international nonproprietary name “vilaprisan” for BAY 1002670, which was implemented.
    26 Sep 2014
    - Per a request from the Swedish authorities, examples of diseases, conditions, and concomitant medications that would exclude a subject from participating in the study were added. - Allowance to include subjects with prior dilation and curettage and myomectomy was added based on feedback from the investigators meeting and an ethics committee. - Changes for statistical analyses were introduced for following exploratory efficacy variables: a. Percentage of subjects with a volume reduction of >/= 25% of the 3 largest fibroids (not the total fibroid volume) measured by MRI and ultrasound b. Evaluation of the CGI-C/PGI-C not only at EoT, but also during the follow-up period. c.Based upon newly available data from PK investigations, the exclusion of grapefruit and grapefruit juice during treatment was added. d. The exclusion of solarium visits during treatment was added. e. Instructions were added to avoid screening subjects who were unlikely to meet the inclusion criterion on heavy bleeding. f. If PAECs were detected in the biopsy at FUP 3, a recommendation to take a new biopsy was added.

    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.
    '99999’ in the posting indicates that data were not available. Decimal places were automatically truncated if last decimal equals zero.
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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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