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    Clinical Trial Results:
    Phase IIa, Double-Blind, Placebo-Controlled, Study of ESN364 Administered for 12 Weeks to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Women Presenting With Polycystic Ovarian Syndrome

    Summary
    EudraCT number
    		 2014-004409-34
    Trial protocol
    		 BE   AT   NL  
    Global end of trial date
    01 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2018
    First version publication date
    12 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ESN364-PCO-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ogeda S.A.
    Sponsor organisation address
    Rue Adrienne Bolland, Gosselies, Belgium, 6047
    Public contact
    Clinical Trial Disclosure, Ogeda S.A, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Ogeda S.A, astellas.resultsdisclosure@astellas.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
    19 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate efficacy of two doses of ESN364 versus placebo when administered for 12 weeks to decrease total testosterone (TT) levels.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization (ICH) Note for Guidance on Good Clinical Practice (GCP) (CPMP/ICH/135/95) and with applicable local requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 May 2015
    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: 10
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Georgia: 7
    Worldwide total number of subjects
    73
    EEA total number of subjects
    66
    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)
    73
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Pre-menopausal woman between 18 and 45 years inclusive at screening, diagnosed with PCOS and biochemical hyperandrogenism mandatory. Oligomenorrhea or oligo-ovulation and polycystic ovaries on ultrasound. In total, 105 subjects were screened of which 73 randomized.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Blinding was achieved by the double-dummy method with placebo identical in smell, taste, and appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ESN364 60 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    ESN364
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    60 mg ESN364 once daily for 12 weeks

    Arm title
    		 ESN364 180 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    ESN364
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    180 mg ESN364 once daily for 12 weeks

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo oral use once daily for 12 weeks

    Number of subjects in period 1
    		ESN364 60 mg ESN364 180 mg Placebo
    Started
    23
    23
    27
    Completed
    21
    17
    26
    Not completed
    2
    6
    1
         Consent withdrawn by subject
    1
    4
    1
         Adverse event, non-fatal
    -
    1
    -
         In and Exclusion criteria not met
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ESN364 60 mg
    Reporting group description
    		 -

    Reporting group title
    ESN364 180 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 ESN364 60 mg ESN364 180 mg Placebo Total
    Number of subjects
    		 23 23 27 73
    Age categorical
    Units: Subjects
        Adults (18 - 45) years
    		 23 23 27 73
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 27 (21 to 41) 26 (19 to 34) 27 (18 to 44) -
    Gender categorical
    Units: Subjects
        Female
    		 23 23 27 73

    End points

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    End points reporting groups
    Reporting group title
    ESN364 60 mg
    Reporting group description
    		 -

    Reporting group title
    ESN364 180 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Efficacy: Change from baseline in Total Testosterone (TT) at Week 12

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    End point title
    		 Efficacy: Change from baseline in Total Testosterone (TT) at Week 12 [1]
    End point description
    Change from baseline in Total Testosterone (TT) at Week 12 Total testerone (nmol/L) Intent-to-treat (ITT) Population: all randomized subjects who received at least one dose of study drug and who have post-baseline efficacy data.
    End point type
    Primary
    End point timeframe
    From baseline through week 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive only
    End point values
    		 ESN364 60 mg ESN364 180 mg Placebo
    Number of subjects analysed
    23 [2]
    23 [3]
    27 [4]
    Units: nmol/L
        arithmetic mean (standard deviation)
    -0.16 ( 0.457 )
    -0.68 ( 0.561 )
    -0.04 ( 0.526 )
    Notes
    [2] - Actual number of participants used in in the analysis = 17
    [3] - Actual number of participants used in in the analysis = 15
    [4] - Actual number of participants used in in the analysis = 24
    No statistical analyses for this end point

    Secondary: Efficacy: Change in Total Testosterone (TT) from baseline to Week 9 (at trough PK levels)

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    End point title
    		 Efficacy: Change in Total Testosterone (TT) from baseline to Week 9 (at trough PK levels)
    End point description
    Change in Total Testosterone (TT) from baseline to Week 9 (at trough PK levels) Actual values in Total testosterone (TT) ITT Population
    End point type
    Secondary
    End point timeframe
    From baseline to Week 9
    End point values
    		 ESN364 60 mg ESN364 180 mg Placebo
    Number of subjects analysed
    23
    23
    27
    Units: Timepoint
    arithmetic mean (standard deviation)
        Baseline
    1.65 ( 0.655 )
    2.16 ( 1.011 )
    2.01 ( 0.803 )
        At Week 6
    1.48 ( 0.727 )
    1.41 ( 0.519 )
    1.91 ( 0.872 )
        At Week 9
    1.58 ( 0.635 )
    1.51 ( 0.405 )
    1.83 ( 0.732 )
    No statistical analyses for this end point

    Secondary: Efficacy: Change in Menstrual Cycle as Measured by Menses

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    End point title
    		 Efficacy: Change in Menstrual Cycle as Measured by Menses
    End point description
    Change in Menstrual Cycle as Measured by Menses Change in frequency of menses per treatment arm and per time point ITT population
    End point type
    Secondary
    End point timeframe
    From treatment (Week 12) to Follow-Up (Week 18)
    End point values
    		 ESN364 60 mg ESN364 180 mg Placebo
    Number of subjects analysed
    23 [5]
    23 [6]
    27 [7]
    Units: Frequency of menses
    arithmetic mean (standard deviation)
        Treatment - Week 12
    1.0 ( 0.93 )
    0.3 ( 0.56 )
    1.6 ( 1.83 )
        Follow-Up - Week 18
    0.4 ( 0.60 )
    0.3 ( 0.45 )
    0.5 ( 0.58 )
    Notes
    [5] - N = 21: Follow-Up - Week 18
    [6] - N = 19: Follow-Up - Week 18
    [7] - N = 26: Follow-Up - Week 18
    No statistical analyses for this end point

    Secondary: Efficacy: Change in Menstrual Cycle as Measured by Spotting

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    End point title
    		 Efficacy: Change in Menstrual Cycle as Measured by Spotting
    End point description
    Change in Menstrual Cycle as Measured by Spotting Change in frequency of spotting per treatment arm and per time point ITT population
    End point type
    Secondary
    End point timeframe
    From treatment (Week 12) until Follow-Up (Week 18)
    End point values
    		 ESN364 60 mg ESN364 180 mg Placebo
    Number of subjects analysed
    23 [8]
    23 [9]
    27 [10]
    Units: Frequency of spotting
    arithmetic mean (standard deviation)
        Treatment - Week 12
    0.4 ( 0.78 )
    0.2 ( 0.39 )
    0.9 ( 1.63 )
        Follow-Up - Week 18
    0.0 ( 0.00 )
    0.2 ( 0.50 )
    0.3 ( 0.67 )
    Notes
    [8] - N = 21: Follow-Up - Week 18
    [9] - N = 19: Follow-up - Week 18
    [10] - N = 26: Follow-Up - Week 18
    No statistical analyses for this end point

    Secondary: Efficacy: Change in Menstrual Cycle as Measured by Inter-Menstrual Bleeding

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    End point title
    		 Efficacy: Change in Menstrual Cycle as Measured by Inter-Menstrual Bleeding
    End point description
    Change in Menstrual Cycle as Measured by Inter-Menstrual Bleeding Changes in frequency of intermenstrual bleeding per treatment arm and time point ITT population
    End point type
    Secondary
    End point timeframe
    From treatment (Week 12) until Follow-Up (Week 18)
    End point values
    		 ESN364 60 mg ESN364 180 mg Placebo
    Number of subjects analysed
    23 [11]
    23 [12]
    27 [13]
    Units: Frequency of intermenstrual bleeding
    arithmetic mean (standard deviation)
        Treatment - Week 12
    0.2 ( 0.39 )
    0.1 ( 0.29 )
    0.4 ( 1.01 )
        Follow-Up - Week 18
    0.3 ( 0.72 )
    0.0 ( 0.00 )
    0.1 ( 0.27 )
    Notes
    [11] - N = 21: Follow-Up - Week 18
    [12] - N = 19: Follow-Up - Week 18
    [13] - N = 26: Follow-Up - Week 18
    No statistical analyses for this end point

    Secondary: Efficacy: Change from Baseline in Polycystic Ovarian Syndrome questionnaire (PCOSQ) score at Week 6 and Week 12

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    End point title
    		 Efficacy: Change from Baseline in Polycystic Ovarian Syndrome questionnaire (PCOSQ) score at Week 6 and Week 12
    End point description
    Change from Baseline in Polycystic Ovarian Syndrome questionnaire (PCOSQ) score per time point. The questions concern health and health-related issues for women with Polycystic Ovary Syndrome on how they feel related to: Emotions, Body hair, Weight, Infertility problems, Menstrual problems. Polysystic Ovary Syndrome Questionnaire (PCOSQ) was used to measure the health-related quality of life (HRQoL), on a scale from 1 to 7, with 1 representing the greatest possible impairment and 7 representing the least impairment. ITT population
    End point type
    Secondary
    End point timeframe
    Week 6 and Week 12 (End of Treatment)
    End point values
    		 ESN364 60 mg ESN364 180 mg Placebo
    Number of subjects analysed
    23
    23
    27
    Units: Score
    arithmetic mean (standard deviation)
        Emotions total score Week 6
    -0.2 ( 0.73 )
    -0.2 ( 0.88 )
    -0.2 ( 0.72 )
        Emotions total score Week 12
    0.0 ( 0.86 )
    -0.6 ( 1.15 )
    -0.1 ( 0.85 )
        Body hair total score Week 6
    -0.1 ( 0.81 )
    -0.2 ( 0.64 )
    -0.5 ( 0.73 )
        Body hair total score Week 12
    -0.1 ( 0.76 )
    -0.3 ( 1.06 )
    -0.3 ( 0.84 )
        Weight total score Week 6
    -0.2 ( 0.71 )
    0.1 ( 1.05 )
    -0.1 ( 1.07 )
        Weight total score Week 12
    -0.4 ( 0.85 )
    0.0 ( 1.07 )
    -0.3 ( 1.09 )
        Infertility problems total score Week 6
    0.3 ( 1.09 )
    0.0 ( 0.95 )
    -0.2 ( 0.99 )
        Infertility problems total score Week 12
    0.1 ( 1.18 )
    -0.6 ( 1.39 )
    0.1 ( 1.22 )
        Menstrual problems total score Week 6
    0.1 ( 1.07 )
    0.5 ( 1.71 )
    0.2 ( 1.06 )
        Menstrual problems total score Week 12
    0.6 ( 1.17 )
    0.3 ( 1.21 )
    0.3 ( 1.29 )
    No statistical analyses for this end point

    Secondary: Efficacy: Change from Baseline in Sex Hormone Level to Week 6, 12 and 18

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    End point title
    		 Efficacy: Change from Baseline in Sex Hormone Level to Week 6, 12 and 18
    End point description
    Change from Baseline in Sex Hormone Level to Week 6, 12 and 18 Change from Baseline in Sex Hormone Concentrations per Time Point Estradiol (E2), Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), Progesterone (P4), LH:FSH ratio, Total Testosterone (TT), Sex Hormone Binding Globulin (SHBG) ITT Population
    End point type
    Secondary
    End point timeframe
    Week 6, Week 12 and Week 18 (Follow Up Period)
    End point values
    		 ESN364 60 mg ESN364 180 mg Placebo
    Number of subjects analysed
    23
    23
    27
    Units: Time point
    arithmetic mean (standard deviation)
        E2 (pmol/L) Week 6
    -134.5 ( 333.38 )
    -45.3 ( 67.74 )
    24.8 ( 383.74 )
        E2 (pmol/L) Week 12
    -106.5 ( 259.44 )
    -88.8 ( 137.52 )
    118.8 ( 645.44 )
        E2 (pmol/L) Follow-up
    -111.7 ( 255.25 )
    -57.0 ( 150.30 )
    7.8 ( 163.10 )
        FSH (IU/L) Week 6
    -0.32 ( 3.598 )
    -0.95 ( 1.206 )
    -0.05 ( 2.153 )
        FSH (IU/L) Week 12
    -1.36 ( 4.078 )
    -1.29 ( 2.090 )
    -0.41 ( 2.139 )
        FSH (IU/L) Follow-up
    -1.33 ( 4.723 )
    -0.25 ( 2.623 )
    -0.33 ( 2.123 )
        LH (mIU/mL) Week 6
    -6.90 ( 17.889 )
    -8.79 ( 6.976 )
    0.24 ( 11.819 )
        LH (mIU/mL) Week 12
    -10.66 ( 16.726 )
    -9.23 ( 9.694 )
    -1.78 ( 6.365 )
        LH (mIU/mL) Follow-up
    -6.82 ( 19.456 )
    -3.69 ( 10.650 )
    -1.84 ( 7.731 )
        P4 (ng/mL) Week 6
    -2.08 ( 4.088 )
    -0.51 ( 1.301 )
    -0.66 ( 2.648 )
        P4 (ng/mL) Week 12
    -1.81 ( 4.719 )
    -0.69 ( 1.275 )
    0.77 ( 6.641 )
        P4 (ng/mL) Follow-up
    -0.98 ( 5.704 )
    -0.36 ( 1.313 )
    0.53 ( 5.243 )
        LH/FSH ratio Week 6
    -1.01 ( 1.699 )
    -1.36 ( 1.131 )
    -0.15 ( 1.150 )
        LH/FSH ratio Week 12
    -1.29 ( 1.754 )
    -1.39 ( 1.188 )
    -0.26 ( 0.829 )
        LH/FSH ratio Follow-up
    -0.50 ( 1.729 )
    -0.66 ( 1.322 )
    -0.32 ( 0.935 )
        TT (nmol/L) Week 6
    -0.15 ( 0.417 )
    -0.94 ( 0.855 )
    -0.10 ( 0.541 )
        TT (nmol/L) Week 12
    -0.16 ( 0.457 )
    -0.68 ( 0.561 )
    -0.04 ( 0.526 )
        TT (nmol/L) Follow-up
    -0.11 ( 0.508 )
    -0.47 ( 0.970 )
    -0.10 ( 0.529 )
        SHBG (nmol/L) Week 6
    -4.73 ( 13.995 )
    -0.25 ( 6.776 )
    -6.91 ( 22.136 )
        SHBG (nmol/L) Week 12
    -3.07 ( 16.282 )
    -3.56 ( 4.581 )
    -3.90 ( 27.926 )
        SHBG (nmol/L) Follow-up
    -3.42 ( 11.667 )
    14.75 ( 47.950 )
    -0.17 ( 38.823 )
    No statistical analyses for this end point

    Secondary: Efficacy: Change from Baseline in Endometrium thickness, Ovarian volume, Number of Follicles (cysts), and Dominant Follicle Development (Y/N) as Assessed by Transvaginal Ultrasound (TVU) from Baseline to Week 6 and Week 12 (end-of-treatment)

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    End point title
    		 Efficacy: Change from Baseline in Endometrium thickness, Ovarian volume, Number of Follicles (cysts), and Dominant Follicle Development (Y/N) as Assessed by Transvaginal Ultrasound (TVU) from Baseline to Week 6 and Week 12 (end-of-treatment)
    End point description
    Change from Baseline in Endometrium thickness, Ovarian volume, Number of Follicles (cysts), and Dominant Follicle Development (Y/N) as Assessed by Transvaginal Ultrasound (TVU) from Baseline to Week 6 and Week 12 (end-of-treatment) Changes from baseline in Transvaginal ultrasound (TVU) Parameters per time point Ovarian volume, Number of follicles, Dominant follicle development, Endometrial thickness ITT Population
    End point type
    Secondary
    End point timeframe
    Week 6 and Week 12
    End point values
    		 ESN364 60 mg ESN364 180 mg Placebo
    Number of subjects analysed
    23
    23
    27
    Units: Number
    arithmetic mean (standard deviation)
        Ovary volume (left, cm^3) Week 6
    -5.358 ( 12.5094 )
    -5.139 ( 21.5367 )
    -0.186 ( 4.5419 )
        Ovary volume (left, cm^3) Week 12
    -2.034 ( 16.3996 )
    -5.985 ( 21.3795 )
    -0.587 ( 4.0751 )
        Ovary volume (right, cm^3) Week 6
    -0.218 ( 5.6906 )
    -9.556 ( 20.4629 )
    -0.542 ( 13.0437 )
        Ovary volume (right, cm^3) Week 12
    0.757 ( 10.2340 )
    -10.646 ( 16.3637 )
    -2.198 ( 7.5347 )
        Number of follicles (left ovary) Week 6
    0.1 ( 7.26 )
    -0.4 ( 11.20 )
    -2.0 ( 8.65 )
        Number of follicles (left ovary) Week 12
    -1.8 ( 8.15 )
    3.7 ( 13.12 )
    -0.7 ( 10.13 )
        Number of follicles (right ovary) Week 6
    -1.0 ( 4.19 )
    -2.1 ( 8.56 )
    -2.1 ( 11.44 )
        Number of follicles (right ovary) Week 12
    0.6 ( 6.63 )
    3.1 ( 12.40 )
    -1.2 ( 9.76 )
        Surface of dominant follicle (mm^2) Week 6
    -145.755 ( 349.8645 )
    -19.832 ( 151.2902 )
    -54.705 ( 113.8735 )
        Surface of dominant follicle (mm^2) Week 12
    -99.185 ( 311.8806 )
    15.560 ( 43.7020 )
    -24.026 ( 153.5590 )
        Endometrial thickness (mm) Week 6
    0.267 ( 1.8330 )
    -0.692 ( 1.8615 )
    0.600 ( 2.9584 )
        Endometrial thickness (mm) Week 12
    0.042 ( 2.6401 )
    -0.752 ( 1.6592 )
    -0.621 ( 2.7920 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment period: From first treatment administration date to last treatment administration date + 6 days with 23.59 added as time part.
    Adverse event reporting additional description
    Treatment-Emergent Adverse Events Safety population: all subjects who were randomized into the study and who used the trial medication at least once were considered evaluable for the safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    ESN364 60 mg
    Reporting group description
    		 60 mg ESN364 once daily for 12 weeks

    Reporting group title
    ESN364 180 mg
    Reporting group description
    		 180 mg ESN364 once daily for 12 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral use once daily for 12 weeks

    Serious adverse events
    		 ESN364 60 mg ESN364 180 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 23 (8.70%)
    0 / 27 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ESN364 60 mg ESN364 180 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 23 (73.91%)
    21 / 23 (91.30%)
    20 / 27 (74.07%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign breast neoplasm
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Fatigue
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 23 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    2
    0
    3
    Impaired healing
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Breast discharge
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Breast discomfort
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Vulvovaginal pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    1
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Depressed mood
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Depression
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Libido decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Nervousness
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Nightmare
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Mood swings
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 23 (8.70%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    Weight increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Congenital, familial and genetic disorders
    Gilbert's syndrome
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Bundle branch block right
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Palpitations
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 23 (8.70%)
    1 / 27 (3.70%)
         occurrences all number
    2
    2
    1
    Headache
         subjects affected / exposed
    5 / 23 (21.74%)
    9 / 23 (39.13%)
    7 / 27 (25.93%)
         occurrences all number
    5
    9
    7
    Migraine
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 23 (0.00%)
    5 / 23 (21.74%)
    0 / 27 (0.00%)
         occurrences all number
    0
    5
    0
    Tension headache
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Tinnitus
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Myopia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 23 (8.70%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Cheilitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 23 (4.35%)
    1 / 27 (3.70%)
         occurrences all number
    2
    1
    1
    Dyspepsia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    3
    0
    1
    Oesophagitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    2
    Alopecia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    1
    Dandruff
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Erythema annulare
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Hair growth abnormal
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Hirsutism
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    2
    Hyperhidrosis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 23 (13.04%)
    1 / 27 (3.70%)
         occurrences all number
    0
    3
    1
    Skin irritation
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 23 (8.70%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    Joint swelling
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Ear infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Folliculitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Infected bite
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 23 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 23 (8.70%)
    5 / 27 (18.52%)
         occurrences all number
    3
    2
    5
    Paronychia
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Pharyngitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 23 (4.35%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 23 (0.00%)
    0 / 23 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 23 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    2
    0
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 23 (4.35%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Sep 2015
    Correction of errors and inconsistencies in the protocol. - Section: 1.3 Clinical Studies: After finalization, errors were found in the CPK-101 CSR. Data taken from the CSR and included in the introduction of this protocol were corrected. - Sections: 7.1.1 Screening Period; 7.1.2 Treatment Period; 7.1.3 Follow-up Period: The subjects need to fast for 8 hours before the screening visit (Visit 1) and before Visits 2, 5, and 7. This was not consistently described throughout the protocol. - Sections: Synopsis, 4.1 Inclusion Criteria; 4.2 Exclusion Criteria: - Sections: 6.2 Prohibited Concomitant Therapies: Clarification of prohibited therapy. - Sections: 5.1 Physical Description of the Study Drug: The protocol stated that certificates of analysis (CoA) would accompany the study drug to the site. This statement was deleted since CoA are not provided to the sites because this is a blinded study and based on the CoA assumptions could be made about the nature of medication kits. - Sections: Time and Events Schedule, 7.1.1 Screening, 7.1.2 Treatment Period, 7.4.1.3 Transvaginal Ultrasound: To allow independent assessment of transvaginal ultrasound (TVU) measurements, TVU images should be transmitted to the independent radiologist (Biomedical Systems) without any measurements that might have been made at the site. This was already described in the Biomedical Systems manual but has now been added to the protocol for clarification. In addition, use of historical TVU at screening will no longer be allowed. TVU will be mandatory at screening (Visit 1) but will only be performed at Visit 2 if the image quality of the screening TVU was insufficient (as judged by the central reader).

    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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