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    Clinical Trial Results:
    A Single-center, Randomized, Open-label, Two-arm Study to Evaluate the Ovarian Function Inhibition of a Monophasic Combined Oral Contraceptive (COC) Containing 15 mg Estetrol (E4) and 3 mg Drospirenone (DRSP) and a Monophasic COC Containing 20mcg Ethinylestradiol (EE)/3 mg DRSP (YAZ®), Administered Orally Once Daily in a 24/4 Day Regimen for Three Consecutive Cycles

    Summary
    EudraCT number
    		 2016-004267-40
    Trial protocol
    		 NL  
    Global end of trial date
    07 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jun 2019
    First version publication date
    19 Jun 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MIT-Es0001-C202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03091595
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mithra Pharmaceuticals
    Sponsor organisation address
    Rue Saint Georges 5-7, Liège, Belgium, 4000
    Public contact
    Mithra Pharmaceuticals SA Pharma Department, Mithra Pharmaceuticals SA, +32 43492822, clinical.trials@mithra.com
    Scientific contact
    Mithra Pharmaceuticals SA Pharma Department, Mithra Pharmaceuticals SA, +32 43492822, clinical.trials@mithra.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
    07 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effects of the 15 mg estetrol (E4)/3 mg drospirenone (DRSP) combination and the 20 mcg ethinylestradiol (EE)/3 mg DRSP used as reference combination on ovarian function inhibition at Treatment Cycle 1 and Treatment Cycle 3
    Protection of trial subjects
    The study was conducted in accordance with the principles of the Declaration of Helsinki in place at the time of study conduct. The study was conducted in compliance with the International Council for Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP) (Committee for Proprietary Medicinal Products [CPMP] guideline CPMP/ICH/135/95), and compliant with the European Union Clinical Trial Directive: Directive 2001/20/EC.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 82
    Worldwide total number of subjects
    82
    EEA total number of subjects
    82
    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)
    82
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were stratified by day of ovulation in the Pre-Treatment Cycle and Body Mass Index. Each participant completed a Screening Visit, a Pre-Treatment Cycle followed by 3 treatment cycles, a Post-Treatment Cycle and a Follow-Up Visit. In case of use of hormonal contraception, at least 1 wash-out cycle was performed prior to treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 15 mg estetrol/3 mg drospirenone
    Arm description
    		 15 mg E4 combined with 3 mg DRSP administered in a 24/4-day regimen. One tablet per day orally for 3 consecutive treatment cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    15 mg estetrol/3 mg drospirenone
    Investigational medicinal product code
    E4/DRSP
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15 mg E4 combined with 3 mg DRSP administered in a 24/4-day regimen (i.e. 24 days of active tablets followed by 4 days of placebo tablets). One tablet per day orally for 3 treatment cycles.

    Arm title
    		 20 mcg ethinylestradiol/3 mg drospirenone
    Arm description
    		 20 mcg EE combined with 3 mg DRSP administered in a 24/4-day regimen. One tablet per day orally for 3 consecutive treatment cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Yaz®
    Investigational medicinal product code
    EE/DRSP
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mcg EE combined with 3 mg DRSP (Yaz®) administered in a 24/4-day regimen (i.e. 24 days of active tablets followed by 4 days of placebo tablets). One tablet per day orally for 3 treatment cycles.

    Number of subjects in period 1
    		15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Started
    41
    41
    Completed
    37
    34
    Not completed
    4
    7
         Adverse event not related to bleeding
    1
    2
         Other
    1
    4
         Protocol deviation
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    15 mg estetrol/3 mg drospirenone
    Reporting group description
    		 15 mg E4 combined with 3 mg DRSP administered in a 24/4-day regimen. One tablet per day orally for 3 consecutive treatment cycles.

    Reporting group title
    20 mcg ethinylestradiol/3 mg drospirenone
    Reporting group description
    		 20 mcg EE combined with 3 mg DRSP administered in a 24/4-day regimen. One tablet per day orally for 3 consecutive treatment cycles.

    Reporting group values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone Total
    Number of subjects
    		 41 41 82
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 41 41 82
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 25.5 ( 4.52 ) 25.7 ( 3.93 ) -
    Gender categorical
    Units: Subjects
        Female
    		 41 41 82
        Male
    		 0 0 0
    Race
    Units: Subjects
        Asian
    		 1 2 3
        Black or African American
    		 1 2 3
        Other
    		 2 2 4
        White
    		 37 35 72
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 2 2
        Not Hispanic or Latino
    		 41 39 80
    Stratum
    Units: Subjects
        BMI ≤30.0 kg/m2 - Ovulation < Day 12
    		 2 2 4
        BMI ≤30.0 kg/m2 - Ovulation < Day 15
    		 7 6 13
        BMI ≤30.0 kg/m2 - Ovulation < Day 18
    		 16 16 32
        BMI ≤30.0 kg/m2 - Ovulation < Day 21
    		 10 10 20
        BMI ≤30.0 kg/m2 - Ovulation < Day 24
    		 3 2 5
        BMI ≤30.0 kg/m2 - Ovulation < Day 27
    		 3 2 5
        BMI >30 kg/m2 - Ovulation < Day 15
    		 0 1 1
        BMI >30 kg/m2 - Ovulation < Day 21
    		 0 1 1
        BMI >30 kg/m2 - Ovulation < Day 24
    		 0 1 1
    Weight
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 66.49 ( 9.024 ) 67.33 ( 12.357 ) -
    Height
    Units: Centimetres
        arithmetic mean (standard deviation)
    		 171.2 ( 7.22 ) 169.2 ( 7.13 ) -
    Body Mass Index
    Units: Kilogram/metre^2
        arithmetic mean (standard deviation)
    		 22.66 ( 2.474 ) 23.49 ( 4.089 ) -

    End points

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    End points reporting groups
    Reporting group title
    15 mg estetrol/3 mg drospirenone
    Reporting group description
    		 15 mg E4 combined with 3 mg DRSP administered in a 24/4-day regimen. One tablet per day orally for 3 consecutive treatment cycles.

    Reporting group title
    20 mcg ethinylestradiol/3 mg drospirenone
    Reporting group description
    		 20 mcg EE combined with 3 mg DRSP administered in a 24/4-day regimen. One tablet per day orally for 3 consecutive treatment cycles.

    Primary: Number of Participants with Ovarian Inhibition at Treatment Cycle 1

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    End point title
    		 Number of Participants with Ovarian Inhibition at Treatment Cycle 1 [1]
    End point description
    Ovulation inhibition was assessed by rating the suppression of the ovaries using the Hoogland score. This score is based on the follicle sizes assessed by transvaginal ultrasonography (TVUS) and the estradiol (E2) and progesterone levels during a pill cycle. The scores range between 1 and 6, with overall ovarian function inhibition indicated by a Hoogland score of less than 4.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 3 to Day 27
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was planned for this endpoint.
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    40 [2]
    41 [3]
    Units: Participants
        1: No Activity
    34
    34
        2: Potential Activity
    3
    4
        3: Non-Active Follicle Like Structure (FLS)
    1
    0
        4: Active FLS
    2
    2
        5: Luteinized Unruptured Follicle (LUF)
    0
    0
        6: Ovulation
    0
    1
    Notes
    [2] - This total is inclusive of participants with analysable results at Treatment Cycle 1.
    [3] - This total is inclusive of participants with analysable results at Treatment Cycle 1.
    No statistical analyses for this end point

    Primary: Number of Participants with Ovarian Inhibition at Treatment Cycle 3

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    End point title
    		 Number of Participants with Ovarian Inhibition at Treatment Cycle 3 [4]
    End point description
    Ovulation inhibition was assessed by rating the suppression of the ovaries using the Hoogland score. This score is based on the follicle sizes assessed by TVUS and the E2 and progesterone levels during a pill cycle. The scores range between 1 and 6, with overall ovarian function inhibition indicated by a Hoogland score of less than 4.
    End point type
    Primary
    End point timeframe
    Cycle 3 Day 3 to Day 27
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analysis was planned for this endpoint.
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    38 [5]
    37 [6]
    Units: Participants
        1: No Activity
    25
    31
        2: Potential Activity
    4
    3
        3: Non-Active Follicle Like Structure (FLS)
    1
    0
        4: Active FLS
    8
    2
        5: Luteinized Unruptured Follicle (LUF)
    0
    0
        6: Ovulation
    0
    1
    Notes
    [5] - This total is inclusive of participants with analysable results at Treatment Cycle 3.
    [6] - This total is inclusive of participants with analysable results at Treatment Cycle 3.
    No statistical analyses for this end point

    Secondary: Serum Level of Luteinizing Hormone (LH)

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    End point title
    		 Serum Level of Luteinizing Hormone (LH)
    End point description
    The participants with available data varied at each specified time point. In the 15 mg E4/3 mg DRSP arm, up to 40 participants had available data. In the 20 mcg EE/3 mg DRSP arm, up to 41 participants had available data.
    End point type
    Secondary
    End point timeframe
    Day 3, 6, 9, 12, 15, 18, 21, 24, 27 of Treatment Cycle 1 and Treatment Cycle 3 and on Day 3 of the Treatment Cycle 2
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    40 [7]
    41 [8]
    Units: mU/mL
    arithmetic mean (standard deviation)
        Cycle 1: Day 03
    6.10 ( 2.325 )
    5.15 ( 1.949 )
        Cycle 1: Day 06
    6.54 ( 3.465 )
    5.32 ( 2.144 )
        Cycle 1: Day 09
    6.18 ( 3.722 )
    4.91 ( 2.573 )
        Cycle 1: Day 12
    5.90 ( 3.493 )
    4.43 ( 2.765 )
        Cycle 1: Day 15
    5.90 ( 3.230 )
    3.72 ( 2.821 )
        Cycle 1: Day 18
    5.21 ( 2.999 )
    3.18 ( 3.380 )
        Cycle 1: Day 21
    4.83 ( 2.845 )
    2.96 ( 3.580 )
        Cycle 1: Day 24
    5.32 ( 3.528 )
    2.48 ( 2.859 )
        Cycle 1: Day 27
    6.16 ( 3.406 )
    3.96 ( 3.059 )
        Cycle 2: Day 03
    6.64 ( 3.358 )
    5.26 ( 2.928 )
        Cycle 3: Day 03
    6.71 ( 3.025 )
    4.66 ( 3.283 )
        Cycle 3: Day 06
    7.22 ( 3.638 )
    4.75 ( 3.474 )
        Cycle 3: Day 09
    6.88 ( 4.140 )
    4.43 ( 4.798 )
        Cycle 3: Day 12
    6.21 ( 3.714 )
    2.72 ( 2.884 )
        Cycle 3: Day 15
    6.29 ( 3.676 )
    2.46 ( 2.796 )
        Cycle 3: Day 18
    5.86 ( 3.300 )
    1.95 ( 2.431 )
        Cycle 3: Day 21
    5.78 ( 3.281 )
    2.11 ( 2.393 )
        Cycle 3: Day 24
    5.64 ( 3.386 )
    1.84 ( 2.267 )
        Cycle 3: Day 27
    6.50 ( 3.251 )
    3.03 ( 3.028 )
    Notes
    [7] - This total is inclusive of participants with analysable results at Day 3 of the Treatment Cycle 1.
    [8] - This total is inclusive of participants with analysable results at Day 3 of the Treatment Cycle 1.
    No statistical analyses for this end point

    Secondary: Serum Level of Follicle Stimulating Hormone (FSH)

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    End point title
    		 Serum Level of Follicle Stimulating Hormone (FSH)
    End point description
    The participants with available data varied at each specified time point. In the 15 mg E4/3 mg DRSP arm, up to 40 participants had available data. In the 20 mcg EE/3 mg DRSP arm, up to 41 participants had available data.
    End point type
    Secondary
    End point timeframe
    Day 3, 6, 9, 12, 15, 18, 21, 24, 27 of Treatment Cycle 1 and Treatment Cycle 3 and on Day 3 of Treatment Cycle 2
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    40 [9]
    41 [10]
    Units: mU/mL
    arithmetic mean (standard deviation)
        Cycle 1: Day 03
    5.19 ( 1.438 )
    4.86 ( 1.619 )
        Cycle 1: Day 06
    5.31 ( 1.915 )
    4.77 ( 1.623 )
        Cycle 1: Day 09
    4.81 ( 1.887 )
    4.31 ( 1.556 )
        Cycle 1: Day 12
    4.68 ( 1.744 )
    3.63 ( 1.425 )
        Cycle 1: Day 15
    4.67 ( 1.922 )
    3.26 ( 1.911 )
        Cycle 1: Day 18
    4.50 ( 1.926 )
    2.71 ( 1.735 )
        Cycle 1: Day 21
    4.33 ( 1.744 )
    2.46 ( 1.825 )
        Cycle 1: Day 24
    4.66 ( 2.045 )
    2.43 ( 1.756 )
        Cycle 1: Day 27
    6.37 ( 2.149 )
    4.96 ( 3.016 )
        Cycle 2: Day 03
    5.72 ( 1.511 )
    4.86 ( 1.606 )
        Cycle 3: Day 03
    5.45 ( 1.495 )
    4.61 ( 1.437 )
        Cycle 3: Day 06
    5.27 ( 1.522 )
    4.00 ( 1.716 )
        Cycle 3: Day 09
    4.94 ( 1.958 )
    3.16 ( 1.842 )
        Cycle 3: Day 12
    4.83 ( 1.922 )
    2.23 ( 1.468 )
        Cycle 3: Day 15
    4.62 ( 1.813 )
    1.95 ( 1.500 )
        Cycle 3: Day 18
    4.50 ( 1.677 )
    1.70 ( 1.520 )
        Cycle 3: Day 21
    4.53 ( 1.766 )
    1.85 ( 1.761 )
        Cycle 3: Day 24
    4.48 ( 1.900 )
    1.86 ( 2.041 )
        Cycle 3: Day 27
    6.52 ( 2.273 )
    3.70 ( 2.931 )
    Notes
    [9] - This includes all participants with analysable results at Day 3 of the Treatment Cycle 1.
    [10] - This includes all participants with analysable results at Day 3 of the Treatment Cycle 1.
    No statistical analyses for this end point

    Secondary: Serum Level of Estradiol (E2)

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    End point title
    		 Serum Level of Estradiol (E2)
    End point description
    The participants with available data varied at each specified time point. In the 15 mg E4/3 mg DRSP arm, up to 40 participants had available data. In the 20 mcg EE/3 mg DRSP arm, up to 41 participants had available data.
    End point type
    Secondary
    End point timeframe
    Day 3, 6, 9, 12, 15, 18, 21, 24, 27 of Treatment Cycle 1 and Treatment Cycle 3 and on Day 3 of Treatment Cycle 2
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    40 [11]
    41 [12]
    Units: pg/mL
    arithmetic mean (standard deviation)
        Cycle 1: Day 03
    19.303 ( 18.7648 )
    13.325 ( 6.1189 )
        Cycle 1: Day 06
    16.588 ( 21.3997 )
    12.981 ( 15.2934 )
        Cycle 1: Day 09
    8.672 ( 6.6284 )
    16.678 ( 31.2045 )
        Cycle 1: Day 12
    8.196 ( 7.3155 )
    18.916 ( 47.7497 )
        Cycle 1: Day 15
    7.818 ( 6.2617 )
    13.454 ( 35.2221 )
        Cycle 1: Day 18
    10.125 ( 14.0052 )
    12.375 ( 39.9830 )
        Cycle 1: Day 21
    8.329 ( 8.4955 )
    9.893 ( 25.9804 )
        Cycle 1: Day 24
    8.819 ( 9.9171 )
    9.409 ( 21.0308 )
        Cycle 1: Day 27
    21.281 ( 24.7604 )
    35.233 ( 44.3946 )
        Cycle 2: Day 03
    32.471 ( 75.3828 )
    34.338 ( 71.8123 )
        Cycle 3: Day 03
    29.149 ( 45.5948 )
    16.805 ( 27.4196 )
        Cycle 3: Day 06
    26.947 ( 44.3196 )
    24.732 ( 65.3223 )
        Cycle 3: Day 09
    23.664 ( 43.6809 )
    29.548 ( 89.5314 )
        Cycle 3: Day 12
    22.382 ( 48.7051 )
    27.450 ( 97.9313 )
        Cycle 3: Day 15
    15.865 ( 27.8212 )
    23.165 ( 80.2365 )
        Cycle 3: Day 18
    12.574 ( 22.9375 )
    20.682 ( 62.6405 )
        Cycle 3: Day 21
    12.339 ( 19.0090 )
    19.666 ( 67.1126 )
        Cycle 3: Day 24
    8.910 ( 8.6778 )
    8.678 ( 22.5650 )
        Cycle 3: Day 27
    21.080 ( 19.1215 )
    23.489 ( 46.2374 )
    Notes
    [11] - This includes all participants with analysable results at Day 3 of the Treatment Cycle 1.
    [12] - This includes all participants with analysable results at Day 3 of the Treatment Cycle 1.
    No statistical analyses for this end point

    Secondary: Serum Level of Progesterone (P)

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    End point title
    		 Serum Level of Progesterone (P)
    End point description
    The participants with available data varied at each specified time point. In the 15 mg E4/3 mg DRSP arm, up to 40 participants had available data. In the 20 mcg EE/3 mg DRSP arm, up to 41 participants had available data.
    End point type
    Secondary
    End point timeframe
    Day 3, 6, 9, 12, 15, 18, 21, 24, 27 of Treatment Cycle 1 and Treatment Cycle 3 and on Day 3 of Treatment Cycle 2
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    40 [13]
    41 [14]
    Units: nmol/L
    arithmetic mean (standard deviation)
        Cycle 1: Day 03
    1.140 ( 0.5528 )
    0.810 ( 0.5416 )
        Cycle 1: Day 06
    0.984 ( 0.6870 )
    0.779 ( 0.5250 )
        Cycle 1: Day 09
    0.958 ( 0.6145 )
    0.790 ( 0.5667 )
        Cycle 1: Day 12
    0.906 ( 0.9826 )
    0.789 ( 0.4851 )
        Cycle 1: Day 15
    1.016 ( 0.7504 )
    1.145 ( 2.5358 )
        Cycle 1: Day 18
    1.026 ( 1.0024 )
    0.759 ( 0.5109 )
        Cycle 1: Day 21
    0.884 ( 0.6721 )
    0.808 ( 0.4573 )
        Cycle 1: Day 24
    0.934 ( 0.7628 )
    1.571 ( 4.9825 )
        Cycle 1: Day 27
    0.790 ( 0.6245 )
    1.163 ( 2.3064 )
        Cycle 2: Day 03
    0.822 ( 0.5094 )
    0.695 ( 0.4436 )
        Cycle 3: Day 03
    0.942 ( 0.5983 )
    0.654 ( 0.4404 )
        Cycle 3: Day 06
    0.999 ( 0.6775 )
    0.716 ( 0.4357 )
        Cycle 3: Day 09
    0.844 ( 0.5113 )
    1.094 ( 1.6176 )
        Cycle 3: Day 12
    0.719 ( 0.3951 )
    0.790 ( 0.5358 )
        Cycle 3: Day 15
    0.791 ( 0.4282 )
    0.826 ( 0.5984 )
        Cycle 3: Day 18
    0.787 ( 0.4776 )
    0.814 ( 0.8053 )
        Cycle 3: Day 21
    0.948 ( 0.5949 )
    0.886 ( 0.7359 )
        Cycle 3: Day 24
    0.878 ( 0.6476 )
    0.861 ( 0.5419 )
        Cycle 3: Day 27
    0.888 ( 0.7096 )
    0.913 ( 0.6235 )
    Notes
    [13] - This includes all participants with analysable results at Day 3 of the Treatment Cycle 1.
    [14] - This includes all participants with analysable results at Day 3 of the Treatment Cycle 1.
    No statistical analyses for this end point

    Secondary: Maximum Endometrial Thickness

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    End point title
    		 Maximum Endometrial Thickness
    End point description
    Endometrial thickness will be measured using TVUS. Maximum endometrial thickness was defined as the largest endometrial thickness during a cycle. The participants with available data varied at each specified time point. In the 15 mg E4/3 mg DRSP arm, up to 40 participants had available data. In the 20 mcg EE/3 mg DRSP arm, up to 41 participants had available data.
    End point type
    Secondary
    End point timeframe
    Pre-Treatment and Day 3 (±1) to Day 27 (±1) of each Cycle
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    40 [15]
    41 [16]
    Units: Millimetres
    arithmetic mean (standard deviation)
        Pre-Treatment Cycle
    9.28 ( 2.158 )
    9.38 ( 2.028 )
        Cycle 1
    6.16 ( 1.482 )
    6.43 ( 2.164 )
        Cycle 2
    4.43 ( 1.360 )
    4.33 ( 1.794 )
        Cycle 3
    6.21 ( 1.617 )
    5.85 ( 1.545 )
        Post-Treatment Cycle
    9.22 ( 2.002 )
    9.14 ( 2.406 )
    Notes
    [15] - This includes all participants with analysable results at Pre-Treatment Cycle.
    [16] - This includes all participants with analysable results at Pre-Treatment Cycle.
    No statistical analyses for this end point

    Secondary: Mean Diameter of the Largest Follicle

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    End point title
    		 Mean Diameter of the Largest Follicle
    End point description
    Return to fertility will be measured by monitoring follicular growth using TVUS and confirmed by serum progesterone. The participants with available data varied at each specified time point. In the 15 mg E4/3 mg DRSP arm, up to 38 participants had available data. On Day 24 in the 15 mg E4/3 mg DRSP arm, no participants has available data as there were no measurements taken after ovulation. In the 20 mcg EE/3 mg DRSP arm, up to 37 participants had available data. N/A results are indicated by '99999'.
    End point type
    Secondary
    End point timeframe
    Day 3 to Day 24 of Post-Treatment Cycle
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    37 [17]
    37 [18]
    Units: Millimeters
    arithmetic mean (standard deviation)
        Day 03
    9.90 ( 3.518 )
    9.57 ( 5.214 )
        Day 06
    12.63 ( 3.380 )
    11.66 ( 4.938 )
        Day 09
    14.86 ( 3.773 )
    13.42 ( 3.614 )
        Day 12
    15.04 ( 5.683 )
    16.74 ( 3.565 )
        Day 15
    11.55 ( 5.220 )
    17.31 ( 5.955 )
        Day 18
    14.09 ( 6.781 )
    12.09 ( 6.683 )
        Day 21
    9.00 ( 2.115 )
    14.31 ( 8.162 )
        Day 24
    99999 ( 99999 )
    11.15 ( 3.889 )
    Notes
    [17] - This includes all participants with analysable results at Day 3 of the Post-Treatment Cycle.
    [18] - This includes all participants with analysable results at Day 3 of the Post-Treatment Cycle.
    No statistical analyses for this end point

    Secondary: Number of Participants who Experience at Least One Treatment-Emergent Adverse Event (TEAE)

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    End point title
    		 Number of Participants who Experience at Least One Treatment-Emergent Adverse Event (TEAE)
    End point description
    A treatment-emergent AE (TEAE) is defined as any event not present prior to the first administration of the study drug or any event already present that worsens in either severity or frequency following exposure to the study drug.
    End point type
    Secondary
    End point timeframe
    Day 1 to Follow-Up Visit (+ 30 days)
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    41 [19]
    41 [20]
    Units: Participants
    38
    37
    Notes
    [19] - This analysis includes all participants who received at least one dose of study medication.
    [20] - This analysis includes all participants who received at least one dose of study medication.
    No statistical analyses for this end point

    Secondary: Number of Participants who Experience Pregnancy During Treatment

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    End point title
    		 Number of Participants who Experience Pregnancy During Treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 to Follow-Up Visit (+ 30 days)
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    41 [21]
    41 [22]
    Units: Participants
    0
    0
    Notes
    [21] - This analysis includes all participants who received at least one dose of study medication.
    [22] - This analysis includes all participants who received at least one dose of study medication.
    No statistical analyses for this end point

    Secondary: Number of Participants who Experience a Clinically Significant Change in Physical Examination Results

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    End point title
    		 Number of Participants who Experience a Clinically Significant Change in Physical Examination Results
    End point description
    Physical examination included • Eyes, ears, nose, throat, including thyroid and neck • Respiratory system • Cardiovascular system • Peripheral vascular system • Gastrointestinal system, including mouth • Musculoskeletal system • Central and peripheral nervous system • Skin • Lymphatic nodes • BMI
    End point type
    Secondary
    End point timeframe
    Day 1 to End of Follow-Up Visit (+ 30 Days)
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    41 [23]
    41 [24]
    Units: Participants
    0
    0
    Notes
    [23] - This analysis includes all participants who received at least one dose of study medication.
    [24] - This analysis includes all participants who received at least one dose of study medication.
    No statistical analyses for this end point

    Secondary: Number of Participants who Experience a Clinically Significant Change in Gynecological Examination Results

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    End point title
    		 Number of Participants who Experience a Clinically Significant Change in Gynecological Examination Results
    End point description
    Gynecological examination included: • Inspection of outer genital region • Inspection of vagina and cervix • Examination of uterus and adnexa by TVUS • Breast examination (clinical)
    End point type
    Secondary
    End point timeframe
    Day 1 to End of Follow-Up Visit (+ 30 Days)
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    41 [25]
    41 [26]
    Units: Participants
    0
    0
    Notes
    [25] - This analysis includes all participants who received at least one dose of study medication.
    [26] - This analysis includes all participants who received at least one dose of study medication.
    No statistical analyses for this end point

    Secondary: Number of Participants who Experience a Clinically Significant Change in Clinical Laboratory Results

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    End point title
    		 Number of Participants who Experience a Clinically Significant Change in Clinical Laboratory Results
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to End of Follow-Up Visit (+ 30 Days)
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    41 [27]
    41 [28]
    Units: Participants
    0
    0
    Notes
    [27] - This analysis includes all participants who received at least one dose of study medication.
    [28] - This analysis includes all participants who received at least one dose of study medication.
    No statistical analyses for this end point

    Secondary: Number of Participants who Experience a Clinically Significant Change in Electrocardiogram (ECG) Results

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    End point title
    		 Number of Participants who Experience a Clinically Significant Change in Electrocardiogram (ECG) Results
    End point description
    Standard 12-lead ECG machines were used.
    End point type
    Secondary
    End point timeframe
    Day 1 to End of Cycle 3
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    41 [29]
    41 [30]
    Units: Participants
    0
    0
    Notes
    [29] - This analysis includes all participants who received at least one dose of study medication.
    [30] - This analysis includes all participants who received at least one dose of study medication.
    No statistical analyses for this end point

    Secondary: Number of Participants who Experience a Clinically Significant Change in Echocardiogram Results

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    End point title
    		 Number of Participants who Experience a Clinically Significant Change in Echocardiogram Results
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to End of Cycle 3 (Day 28)
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    41 [31]
    41 [32]
    Units: Participants
    0
    0
    Notes
    [31] - This analysis includes all participants who received at least one dose of study medication.
    [32] - This analysis includes all participants who received at least one dose of study medication.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Diastolic Blood Pressure

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    End point title
    		 Change from Baseline in Diastolic Blood Pressure
    End point description
    The participants with available data varied at each specified time point. In the 15 mg E4/3 mg DRSP arm, up to 41 participants had available data. In the 20 mcg EE/3 mg DRSP arm, up to 40 participants had available data.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3 and Follow-up Visit
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    41 [33]
    39 [34]
    Units: mmHg
    arithmetic mean (standard deviation)
        Cycle 1
    -0.8 ( 6.37 )
    -1.3 ( 5.79 )
        Cycle 2
    -0.7 ( 6.30 )
    -0.9 ( 6.25 )
        Cycle 3
    0.4 ( 6.24 )
    -0.6 ( 5.87 )
        Follow-up
    -1.8 ( 8.25 )
    0.1 ( 5.99 )
    Notes
    [33] - This includes all participants who received at least one dose of study drug with results at Cycle 1.
    [34] - This includes all participants who received at least one dose of study drug with results at Cycle 1.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Systolic Blood Pressure

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    End point title
    		 Change from Baseline in Systolic Blood Pressure
    End point description
    The participants with available data varied at each specified time point. In the 15 mg E4/3 mg DRSP arm, 41 to 37 participants had available data. In the 20 mcg EE/3 mg DRSP arm, 40 to 37 participants had available data.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3 and Follow-up Visit
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    41 [35]
    39 [36]
    Units: mmHg
    arithmetic mean (standard deviation)
        Cycle 1
    0.6 ( 8.29 )
    -1.7 ( 6.16 )
        Cycle 2
    -1.6 ( 10.81 )
    -1.8 ( 7.13 )
        Cycle 3
    0.3 ( 7.38 )
    -2.7 ( 7.10 )
        Follow-up
    2.8 ( 8.59 )
    3.3 ( 7.36 )
    Notes
    [35] - This includes all participants who received at least one dose of study drug with results at Cycle 1.
    [36] - This includes all participants who received at least one dose of study drug with results at Cycle 1.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pulse Rate

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    End point title
    		 Change from Baseline in Pulse Rate
    End point description
    The participants with available data varied at each specified time point. In the 15 mg E4/3 mg DRSP arm, 37 to 41 participants had available data. In the 20 mcg EE/3 mg DRSP arm, 37 to 40 participants had available data.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3 and Follow-up Visit
    End point values
    		 15 mg estetrol/3 mg drospirenone 20 mcg ethinylestradiol/3 mg drospirenone
    Number of subjects analysed
    41 [37]
    39 [38]
    Units: Beats/min
    arithmetic mean (standard deviation)
        Cycle 1
    -0.3 ( 11.14 )
    -0.6 ( 11.17 )
        Cycle 2
    0.9 ( 11.63 )
    -0.5 ( 10.21 )
        Cycle 3
    2.8 ( 12.66 )
    1.6 ( 9.93 )
        Follow-up
    0.6 ( 10.63 )
    1.8 ( 10.09 )
    Notes
    [37] - This includes all participants who received at least one dose of study drug with results at Cycle 1.
    [38] - This includes all participants who received at least one dose of study drug with results at Cycle 1.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to End of Follow-Up Visit (+30 days)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    20 mcg EE/3 mg DRSP
    Reporting group description
    		 -

    Reporting group title
    15 mg E4/3 mg DRSP
    Reporting group description
    		 -

    Serious adverse events
    		 20 mcg EE/3 mg DRSP 15 mg E4/3 mg DRSP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 41 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 20 mcg EE/3 mg DRSP 15 mg E4/3 mg DRSP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 41 (90.24%)
    38 / 41 (92.68%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 41 (7.32%)
         occurrences all number
    1
    3
    Surgical and medical procedures
    Dental care
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    0
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 41 (34.15%)
    12 / 41 (29.27%)
         occurrences all number
    24
    26
    Dizziness
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 41 (2.44%)
         occurrences all number
    3
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 41 (9.76%)
    3 / 41 (7.32%)
         occurrences all number
    4
    3
    Malaise
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 41 (2.44%)
         occurrences all number
    4
    1
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    9 / 41 (21.95%)
    9 / 41 (21.95%)
         occurrences all number
    12
    10
    Nausea
         subjects affected / exposed
    9 / 41 (21.95%)
    6 / 41 (14.63%)
         occurrences all number
    10
    6
    Diarrhoea
         subjects affected / exposed
    3 / 41 (7.32%)
    6 / 41 (14.63%)
         occurrences all number
    3
    9
    Vomiting
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    6 / 41 (14.63%)
    13 / 41 (31.71%)
         occurrences all number
    8
    22
    Breast enlargement
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 41 (9.76%)
         occurrences all number
    1
    4
    Dysmenorrhoea
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    4 / 41 (9.76%)
    2 / 41 (4.88%)
         occurrences all number
    5
    2
    Cough
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 41 (2.44%)
         occurrences all number
    3
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 41 (7.32%)
         occurrences all number
    2
    3
    Eczema
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 41 (2.44%)
         occurrences all number
    6
    1
    Psychiatric disorders
    Affect lability
         subjects affected / exposed
    3 / 41 (7.32%)
    5 / 41 (12.20%)
         occurrences all number
    3
    6
    Mood swings
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 41 (9.76%)
    5 / 41 (12.20%)
         occurrences all number
    4
    7
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    12 / 41 (29.27%)
    16 / 41 (39.02%)
         occurrences all number
    14
    19
    Influenza
         subjects affected / exposed
    7 / 41 (17.07%)
    11 / 41 (26.83%)
         occurrences all number
    8
    11
    Gastroenteritis
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 41 (7.32%)
         occurrences all number
    4
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jan 2017
    Protocol Version 2.0 The changes introduced were items observed during preparation of the study. • Update of signatories and addition of contact details of additional laboratories. • Clarification of the timing of clinical laboratory assessments at early-termination visit. • Clarification of Exclusion Criteria #37 and #41.
    09 Mar 2017
    Protocol Version 3.0 The changes introduced were: • Clarification of Inclusion Criterion #5 where only routine clinical laboratory should be considered. • Clarification of the reference to routine clinical laboratory and cardiac markers where applicable. • Administrative change was made to the signatories.
    22 Nov 2017
    Protocol Version 4.0 The laboratory for routine clinical safety laboratory was changed from QPS Holdings, LLC to Analytical Biochemical Laboratory BV.

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

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