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    Clinical Trial Results:
    Pilot/Phase IIa Trial to Investigate the Effect of ESN364 in Early Postmenopausal Women Suffering From Hot Flashes

    Summary
    EudraCT number
    2015-002578-20
    Trial protocol
    BE  
    Global end of trial date
    06 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Nov 2017
    First version publication date
    15 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ESN364-HF-204
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ogeda S.A.
    Sponsor organisation address
    47 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
    06 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the effect of ESN364 on the severity and frequency of hot flashes (HF) in early postmenopausal women suffering from HF, in terms of changes in weekly Hot Flash Score (HFS) from baseline to Week 12.
    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 Conference on 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
    21 Sep 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
    Belgium: 87
    Worldwide total number of subjects
    87
    EEA total number of subjects
    87
    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)
    87
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Women between 40-65 yrs with spontaneous amenorrhea for at least 12 consecutive M or at least 6M with biochemical criteria of menopause or had bilateral oophorectomy, who have experienced at least 49 moderate or severe HF or night sweats over a period of 7 consecutive days; with at least 4 of those days with 7 or more moderate or severe HF per day.

    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
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst
    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
    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
    Subjects received 90 mg of ESN364 orally twice a day 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
    Subjects received 90 mg of placebo orally twice a day for 12 weeks.

    Number of subjects in period 1
    ESN364 Placebo
    Started
    43
    44
    Completed
    40
    40
    Not completed
    3
    4
         Subject continued to have too many hot flashes
    -
    1
         Incl/Excl. criteria not met
    -
    1
         Personal reason
    1
    -
         Adverse event, non-fatal
    2
    -
         Consent withdrawn by subject
    -
    2

    Baseline characteristics

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

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    ESN364 Placebo Total
    Number of subjects
    43 44 87
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    43 44 87
    Gender categorical
    Units: Subjects
        Female
    43 44 87

    End points

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

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: Change from baseline to Week 12 in weekly Hot Flash Score (HFS).

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    End point title
    Change from baseline to Week 12 in weekly Hot Flash Score (HFS).
    End point description
    The HFS was based on the hot flash severity and frequency which were assessed at a minimum twice a day. The HFS was calculated as the (number of mild HF/day × 1) + (number of moderate HF/day × 2) + (number of severe HF/day × 3). Higher scores indicated worse symptoms. The analysis population was Intent-to-treat (ITT) and it consisted of all randomized subjects who received at least one dose of the study medication and subjects who have had post-baseline efficacy data.
    End point type
    Primary
    End point timeframe
    From baseline through week 12
    End point values
    ESN364 Placebo
    Number of subjects analysed
    43
    44
    Units: Change from baseline to week 12
        arithmetic mean (confidence interval 95%)
    -26.51 (-30.83 to -22.18)
    -12.19 (-16.55 to -7.83)
    Statistical analysis title
    ANCOVA result Week 12
    Comparison groups
    ESN364 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -12.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.89
         upper limit
    -7.79
    Notes
    [1] - P-value: < 0.001

    Secondary: Change from baseline over time in weekly HF severity score (Method 1).

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    End point title
    Change from baseline over time in weekly HF severity score (Method 1).
    End point description
    Method 1 takes into account the number and severity of moderate and severe HF occurred during a given time period. The Hot Flash Severity score (based on severity and frequency) was calculated as follows: HF Severity score = [(number of moderate hot flashes/day × 2) + (number of severe hot flashes/day × 3)]/(#moderate HF + #severe HF) The weekly hot flash severity was calculated: Mean HF Severity day-score over 1 week Higher scores indicate worse symptoms. For weekly HF severity score calculated by method 1 the maximum was 3 (the maximum is attained when all HF are severe). The analysis population was Intent-to-treat (ITT).
    End point type
    Secondary
    End point timeframe
    From baseline to week 12
    End point values
    ESN364 Placebo
    Number of subjects analysed
    43
    44
    Units: Change from baseline to week 12
    arithmetic mean (confidence interval 95%)
        Change from baseline to week 12
    -1.656 (-1.937 to -1.376)
    -0.534 (-0.798 to -0.270)
    Statistical analysis title
    ANCOVA result Week 12
    Comparison groups
    ESN364 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [2]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -1.122
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.504
         upper limit
    -0.741
    Notes
    [2] - P-value: < 0.001

    Secondary: Change from baseline over time in weekly HF severity score (Method 2).

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    End point title
    Change from baseline over time in weekly HF severity score (Method 2).
    End point description
    Method 2 (as recommended by FDA) takes into account moderate and severe HF during a given time period. The Hot Flash Severity (based on severity and frequency) was calculated as follows: HF Severity day-score = [(number of moderate hot flashes/day × 2) + (number of severe hot flashes/day × 3)] The weekly hot flash severity was calculated: Mean HF Severity day-score over 1 week Higher scores indicate worse symptoms. There was no maximum score since the number of HF does not have an upper limit. The analysis population was Intent-to-treat (ITT).
    End point type
    Secondary
    End point timeframe
    From baseline through week 12
    End point values
    ESN364 Placebo
    Number of subjects analysed
    43
    44
    Units: Change from baseline to week 12
    arithmetic mean (confidence interval 95%)
        Change from baseline to week 12
    -26.61 (-31.06 to -22.17)
    -12.14 (-16.62 to -7.65)
    Statistical analysis title
    ANCOVA result Week 12
    Comparison groups
    Placebo v ESN364
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [3]
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -12.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17
         upper limit
    -7.83
    Notes
    [3] - P-value: < 0.001

    Secondary: Changes from baseline over time in weekly HF severity score and Hot Flash Frequency (all severities).

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    End point title
    Changes from baseline over time in weekly HF severity score and Hot Flash Frequency (all severities).
    End point description
    HF frequency for all severities scores were calculated by method 1: Method 1 takes into account the number and severity of moderate and severe HF occurred during a given time period. The Hot Flash Severity score (based on severity and frequency) was calculated as follows: HF Severity score = [(number of moderate hot flashes/day × 2) + (number of severe hot flashes/day × 3)]/(#moderate HF + #severe HF) The weekly hot flash severity was calculated: Mean HF Severity day-score over 1 week Higher scores indicate worse symptoms. For weekly HF severity score calculated by method 1 the maximum was 3. The analysis population was Intent-to-treat (ITT).
    End point type
    Secondary
    End point timeframe
    From baseline through week 12
    End point values
    ESN364 Placebo
    Number of subjects analysed
    43
    44
    Units: Change from baseline to week 12
    arithmetic mean (confidence interval 95%)
        Change from baseline to week 12
    -75.3 (-86.4 to -64.3)
    -35.6 (-46.7 to -24.5)
    Statistical analysis title
    ANCOVA result Week 12
    Comparison groups
    Placebo v ESN364
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [4]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -47.9
         upper limit
    -22.1
    Notes
    [4] - P-value: < 0.001

    Secondary: Changes from baseline over time in weekly HF severity score and Hot Flash Frequency (moderate & severe).

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    End point title
    Changes from baseline over time in weekly HF severity score and Hot Flash Frequency (moderate & severe).
    End point description
    HF frequency for moderate and severe scores were calculated by method 2: Method 2 (as recommended by FDA) takes into account moderate and severe HF during a given time period. The Hot Flash Severity (based on severity and frequency) was calculated as follows: HF Severity day-score = [(number of moderate hot flashes/day × 2) + (number of severe hot flashes/day × 3)] The weekly hot flash severity was calculated: Mean HF Severity day-score over 1 week Higher scores indicate worse symptoms. There was no maximum score since the number of HF does not have an upper limit. The analysis population was Intent-to-treat (ITT).
    End point type
    Secondary
    End point timeframe
    From baseline to week 12
    End point values
    ESN364 Placebo
    Number of subjects analysed
    43
    44
    Units: Change from baseline to week 12
    arithmetic mean (confidence interval 95%)
        Change from baseline to week 12
    -76.1 (-87.2 to -0.65)
    -35.3 (-46.9 to -23.6)
    Statistical analysis title
    ANCOVA result Week 12
    Comparison groups
    ESN364 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [5]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -35.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -47.6
         upper limit
    -22.8
    Notes
    [5] - P-value: < 0.001

    Secondary: Change in overall mean score from baseline over time in Hot Flash Related daily Interference Scale (HFRDIS).

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    End point title
    Change in overall mean score from baseline over time in Hot Flash Related daily Interference Scale (HFRDIS).
    End point description
    The HFRDIS was completed at the clinical site in the ePRO diary, at any time during the visit. The HFRDIS is a 10-item scale which measures a woman’s perceptions of the degree to which hot flashes interfere with 9 daily life activities (work, social activities, leisure, sleep, mood, concentration, relations with others, sexuality, enjoying life); the 10th item measures interference with overall quality of life. This scale was modeled after items on the Brief Pain Inventory and Brief Fatigue Inventory, both of which assess the extent to which pain or fatigue interfere with daily life. Subjects were asked to rate the extent to which hot flashes have interfered with each item during the previous 4-week time interval using a 0 (do not interfere) to 10 (completely interfere) scale. The overall mean score is presented. The analysis population was Intent-to-treat (ITT).
    End point type
    Secondary
    End point timeframe
    From baseline and week 12
    End point values
    ESN364 Placebo
    Number of subjects analysed
    43
    44
    Units: Overall mean score
    arithmetic mean (confidence interval 95%)
        Baseline
    5.29 (4.69 to 5.89)
    5.02 (4.46 to 5.58)
        Week 12
    1.12 (0.71 to 1.53)
    3.03 (2.23 to 3.83)
    Statistical analysis title
    ANCOVA result Week 12
    Comparison groups
    ESN364 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [6]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -1.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.83
         upper limit
    -1.13
    Notes
    [6] - P-value: < 0.001

    Secondary: Changes from baseline over time in Leeds Sleep Evaluation Questionnaire (LSEQ).

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    End point title
    Changes from baseline over time in Leeds Sleep Evaluation Questionnaire (LSEQ).
    End point description
    The subjects’ sleep quality was evaluated every 4 weeks from the start of study drug intake (Visit 2) through the follow-up visit (Visit 6) using the LSEQ. The LSEQ is a visual analogue scale which requires respondents to place marks on a group of 10-cm lines representing the changes they have experienced in a variety of symptoms since the beginning of treatment. The LSEQ is a visual analogue scale which requires respondents to place marks on a group of 10-cm lines representing the changes they have experienced in a variety of symptoms since the beginning of treatment.Lines extend between extremes like “more difficult than usual” and “easier than usual”. Responses were measured using a 100-mm scale and are averaged to provide a score for each domain. The analysis population was Intent-to-treat (ITT).
    End point type
    Secondary
    End point timeframe
    From baseline and week 12
    End point values
    ESN364 Placebo
    Number of subjects analysed
    43
    44
    Units: LSEQ score
    arithmetic mean (confidence interval 95%)
        Getting to sleep - baseline
    3.872 (3.318 to 4.426)
    3.869 (3.391 to 4.348)
        Getting to sleep - week 12
    6.104 (5.615 to 6.594)
    5.197 (4.672 to 5.722)
        Quality of sleep - baseline
    2.691 (1.936 to 3.445)
    2.390 (1.850 to 2.929)
        Quality of sleep - week 12
    6.767 (6.054 to 7.479)
    4.332 (3.481 to 5.183)
        Awake following sleep - baseline
    3.740 (3.070 to 4.409)
    4.273 (3.700 to 4.846)
        Awake following sleep - week 12
    6.341 (5.601 to 7.081)
    5.256 (4.588 to 5.925)
        Behaviour following wakening - baseline
    3.728 (3.093 to 4.363)
    4.112 (3.549 to 4.675)
        Behaviour following wakening - week 12
    6.162 (5.439 to 6.884)
    5.356 (4.699 to 6.013)
    Statistical analysis title
    Getting to sleep - Ancova result week 12
    Comparison groups
    Placebo v ESN364
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.014
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    0.895
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    1.599
    Statistical analysis title
    Quality of sleep - Ancova result week 12
    Comparison groups
    ESN364 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [7]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    2.433
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.334
         upper limit
    3.532
    Notes
    [7] - P-value: < 0.001
    Statistical analysis title
    Awake following sleep - Ancova result week 12
    Comparison groups
    ESN364 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.031
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    1.113
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.107
         upper limit
    2.12
    Statistical analysis title
    Behaviour following wakening-Ancova result week 12
    Comparison groups
    ESN364 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.084
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    0.842
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.116
         upper limit
    1.8

    Secondary: Changes from baseline over time in Greene Climacteric Scale (GCS).

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    End point title
    Changes from baseline over time in Greene Climacteric Scale (GCS).
    End point description
    Changes in climacteric symptoms was evaluated every 4 weeks from the start of study drug intake (Visit 2) through the follow-up visit (Visit 6) using the GCS. The questionnaire was paper-based, administered at the clinical site at any time during the visit. The GCS is a 21-item scale which provides a brief but comprehensive and valid measure of climacteric symptomatology. Each item was rated by the subject according to its severity using a four-point rating scale from 0 (none) to 3 (severe). The first 20 items of the scale combine into three main independent symptom measures: psychological symptoms (items 1 to 11; score 0 to 33), physical symptoms (items 12 to 18; score 0 to 21), and vasomotor symptoms (items 19 to 20; score 0 to 6), by summing up the individual item scores. Item 21 was a probe for sexual dysfunction. The total score range was 0 to 63. Higher scores indicate worse symptoms. The analysis population was Intent-to-treat (ITT).
    End point type
    Secondary
    End point timeframe
    From baseline and week 12
    End point values
    ESN364 Placebo
    Number of subjects analysed
    43
    44
    Units: GCS score
    arithmetic mean (confidence interval 95%)
        Total GSC score - baseline
    21.9 (18.5 to 25.4)
    21.0 (17.8 to 24.2)
        Total GSC score - week 12
    8.5 (5.9 to 11.1)
    14.6 (11.6 to 17.6)
    Statistical analysis title
    Total GCS score - Ancova results week 12
    Comparison groups
    ESN364 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [8]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -6.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.9
         upper limit
    -2.8
    Notes
    [8] - P-value: < 0.001

    Secondary: Changes from baseline over time in Sheehan Disability Scale (SDS).

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    End point title
    Changes from baseline over time in Sheehan Disability Scale (SDS).
    End point description
    The subjects’ functional impairment of life was evaluated every 4 weeks from the start of study drug intake (Visit 2) through the follow-up visit (Visit 6) using the SDS. The questionnaire will be paper-based, administered at the clinical site at any time during the visit. The SDS is a composite of 3 self-rated items designed to measure the extent to which 3 major sectors in a patient’s life are impaired by panic, anxiety, phobic, or depressive symptoms. The patient rates the extent to which his/her 1- work/school, 2- social life, and 3- family life are impaired by his/her symptoms on a 10-point visual analog scale. The 3 items may be summed into a single dimensional measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired). The analysis population was Intent-to-treat (ITT).
    End point type
    Secondary
    End point timeframe
    From baseline and week 12
    End point values
    ESN364 Placebo
    Number of subjects analysed
    43
    44
    Units: SDS score
    arithmetic mean (confidence interval 95%)
        Global functional impairment - baseline
    14.3 (12.2 to 16.3)
    11.8 (9.7 to 13.8)
        Global functional impairment - week 12
    2.1 (0.9 to 3.2)
    6.8 (4.4 to 9.2)
    Statistical analysis title
    Global functional impairment-Ancova result week 12
    Comparison groups
    ESN364 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [9]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -5.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.8
         upper limit
    -2.8
    Notes
    [9] - P-value: < 0.001

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment period: week 1 to 12
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    ESN364
    Reporting group description
    Subjects received 90 mg of ESN364 orally twice a day for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received 90 mg of placebo orally twice a day for 12 weeks.

    Serious adverse events
    ESN364 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Upper limb fracture
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ESN364 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 43 (67.44%)
    34 / 44 (77.27%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Meniscus operation
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    Inflammation
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Burnout syndrome
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Depressed mood
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    Depression
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    Insomnia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Irritability
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Nipple pain
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    2
    Uterine haemorrhage
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Vaginal discharge
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 44 (4.55%)
         occurrences all number
    1
    2
    Vulvovaginal dryness
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Rib fracture
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Electrocardiogram QT interval abnormal
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    White blood cell count increased
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 44 (4.55%)
         occurrences all number
    3
    2
    Tachycardia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    7 / 43 (16.28%)
    6 / 44 (13.64%)
         occurrences all number
    7
    6
    Migraine
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 44 (2.27%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 44 (0.00%)
         occurrences all number
    3
    0
    Dry mouth
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Intestinal obstruction
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    Paraesthesia oral
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    Sensitivity of teeth
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Tongue ulceration
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    Pruritus
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    Pruritus generalised
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 44 (2.27%)
         occurrences all number
    2
    1
    Arthritis
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 44 (6.82%)
         occurrences all number
    0
    3
    Back pain
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    2
    Bursitis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Fibromyalgia
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    Muscle rigidity
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Myositis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Patellofemoral pain syndrome
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Cystitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    2
    Influenza
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 44 (2.27%)
         occurrences all number
    3
    1
    Lung infection
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 44 (9.09%)
         occurrences all number
    1
    4
    Oral candidiasis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Pulpitis dental
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    Skin infection
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    Subcutaneous abscess
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    Vaginal infection
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Dec 2015
    The overall reason for the revision is to liberalize the participant selection criteria to facilitate recruitment, and to allow for a lower number of subjects to be included in the interim analysis. For a detailed overview of the changes, please refer to the Protocol Amendment section of the full CSR.

    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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