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    Clinical Trial Results:
    Developmental Clinical Studies - Reversing endometrial glucocorticoid deficiency in heavy menstrual bleeding

    Summary
    EudraCT number
    		 2012-003405-98
    Trial protocol
    		 GB  
    Global end of trial date
    29 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jan 2020
    First version publication date
    01 Jan 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    dexFEMv2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01769820
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ACCORD University of Edinburgh & NHS Lothian
    Sponsor organisation address
    QMRI 49 Little France Cres, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    ACCORD enquiries, Research Governance & QA Office, +44 01312426226, enquiries@accord.scot
    Scientific contact
    Ray French, Research Governance & QA Office, +44 01312426226, resgov@accord.scot
    Sponsor organisation name
    ACCORD NHS Lothian
    Sponsor organisation address
    QMRI, 49 LIttle France Cres, Edinburgh, United Kingdom,
    Public contact
    Enquiries, ACCORD, NHS Lothian, +44 1312423328, enquiries@accord.scot
    Scientific contact
    Fiona McArdle, ACCORD, NHS Lothian, +44 1312423328, enquiries@accord.scot
    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
    03 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Work-up studies (Studies 1&2): To gather preliminary safety and efficacy data from first-in-Heavy Menstrual Bleeding use of oral dexamethasone, in women suffering from objectively verified Heavy Menstrual Bleeding (HMB) Adaptive RCT (Study 3): To identify the optimal dose of oral dexamethasone for reduction of Heavy Menstrual Bleeding in women with objectively verified HMB.
    Protection of trial subjects
    Trial was carried out under Medicines for Human Use (Clinical Trials) Regulations and ICH GCP. Trial participants were supported throughout the trial by experienced research nurses and clinical researchers.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Dec 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 107
    Worldwide total number of subjects
    107
    EEA total number of subjects
    107
    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)
    107
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment to the adaptive randomised trial took place between 2014 and 2018. First patient was consented for screening on 29/01/2014, first patient randomised on 01/07/2014 and the last visit for last patient was on 29/03/2018.

    Pre-assignment
    Screening details
    		 Recruitment in Lothian (Scotland) via gynaecology outpatient clinics; family medicine; media advertising. Women aged 18 years or over; reporting regular 28-42 day menstrual cycles; complaining of Heavy Menstrual Bleeding; with measured volume of menstrual blood loss (MBL) across two screening cycles (menstrual periods) averaging ≥ 50mL.

    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
    Blinding implementation details
    Computer-generated pseudo-random numbers were used to generate the randomised allocation sequence. A web-based randomisation system ensured the allocation sequence was concealed from researchers, clinical staff and participants. To maintain concealment, bulk supplies of placebo and Dexamethasone were held by hospital pharmacy who dispensed trial medication in bottles labelled with a unique randomisation number from the list provided by the Edinburgh clinical trials unit.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 placebo
    Arm description
    		 placebo capsule taken orally, twice daily over 5 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    PLacebo capsule, Lactose Ph Eur, taken twice daily over 5 days

    Arm title
    		 Dexamethasone 0.4mg
    Arm description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.4mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    twice daily Dexamethasone 0.2mg over 5 days ; total dose 0.4mg

    Arm title
    		 Dexamethasone 0.8mg
    Arm description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.8mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    twice daily oral Dexamethasone 0.4mg; total daily dose 0.8mg

    Arm title
    		 Dexamethasone 1.0mg
    Arm description
    		 Dexamethasone taken orally twice daily over 5 days: total daily dose is 1.0mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone 0.5mg taken orally twice daily over 5 days;total dose 1.0mg

    Arm title
    		 Dexamethasone 1.2mg
    Arm description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.2mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone 0.6mg taken orally twice daily;total dose 1.2mg

    Arm title
    		 Dexamethasone 1.5mg
    Arm description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.5mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone 0.75mg taken orally twice daily;total dose 1.5mg

    Arm title
    		 Dexamethasone 1.8mg
    Arm description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.8mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone 0.9mg taken orally twice daily;total dose 1.8mg

    Number of subjects in period 1
    		placebo Dexamethasone 0.4mg Dexamethasone 0.8mg Dexamethasone 1.0mg Dexamethasone 1.2mg Dexamethasone 1.5mg Dexamethasone 1.8mg
    Started
    27
    6
    9
    23
    9
    15
    18
    Completed
    23
    5
    9
    21
    8
    14
    16
    Not completed
    4
    1
    0
    2
    1
    1
    2
         Physician decision
    2
    1
    -
    1
    -
    -
    -
         Consent withdrawn by subject
    2
    -
    -
    1
    -
    1
    2
         Lost to follow-up
    -
    -
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    placebo
    Reporting group description
    		 placebo capsule taken orally, twice daily over 5 days.

    Reporting group title
    Dexamethasone 0.4mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.4mg

    Reporting group title
    Dexamethasone 0.8mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.8mg

    Reporting group title
    Dexamethasone 1.0mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days: total daily dose is 1.0mg

    Reporting group title
    Dexamethasone 1.2mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.2mg

    Reporting group title
    Dexamethasone 1.5mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.5mg

    Reporting group title
    Dexamethasone 1.8mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.8mg

    Reporting group values
    		 placebo Dexamethasone 0.4mg Dexamethasone 0.8mg Dexamethasone 1.0mg Dexamethasone 1.2mg Dexamethasone 1.5mg Dexamethasone 1.8mg Total
    Number of subjects
    		 27 6 9 23 9 15 18 107
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 27 6 9 23 9 15 18 107
        From 65-84 years
    		 0 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0 0
    Age continuous
    Mean age at baseline
    Units: years
        arithmetic mean (standard deviation)
    		 40.6 ± 9.1 42.2 ± 11.6 38.3 ± 8.5 39.9 ± 6.9 44.4 ± 3.5 40 ± 9.3 42.6 ± 8.3 -
    Gender categorical
    gender - all female
    Units: Subjects
        Female
    		 27 6 9 23 9 15 18 107
        Male
    		 0 0 0 0 0 0 0 0
    Ethnicity
    ethnic group
    Units: Subjects
        White
    		 26 6 9 22 7 13 16 99
        Mixed
    		 0 0 0 0 1 0 0 1
        Asian
    		 0 0 0 1 1 1 0 3
        African
    		 1 0 0 0 0 0 1 2
        caribbean
    		 0 0 0 0 0 0 1 1
        Not disclosed
    		 0 0 0 0 0 1 0 1
    Smoking history
    Units: Subjects
        Current
    		 6 3 1 0 0 1 3 14
        Previous
    		 3 1 1 7 3 4 3 22
        never
    		 18 2 7 16 6 10 12 71
    No. of births (if applicable)
    Units: Subjects
        None
    		 10 1 2 8 5 4 5 35
        one
    		 3 1 2 5 1 5 2 19
        two
    		 9 3 3 5 0 5 6 31
        three
    		 4 1 2 3 2 1 4 17
        four
    		 0 0 0 2 1 0 1 4
        five
    		 0 0 0 0 0 0 0 0
        six
    		 1 0 0 0 0 0 0 1
    Patient has painful periods
    Units: Subjects
        yes
    		 21 5 4 18 6 14 11 79
        no
    		 6 1 5 5 3 1 7 28
    no. years HMB has been a problem
    Units: years
        arithmetic mean (standard deviation)
    		 8 ± 7.1 4.4 ± 4.1 9.2 ± 5.9 9.2 ± 9.1 12.2 ± 12.4 11.5 ± 11.6 7.1 ± 8.9 -
    Minimum duration menses over past 3 mnths
    Units: days
        arithmetic mean (standard deviation)
    		 6.1 ± 2.8 7.2 ± 4 4.7 ± 1.1 6.1 ± 2.6 5.3 ± 0.9 5.4 ± 1.7 5.2 ± 1.2 -
    Maximum duration menses over past 3 mnths
    Units: days
        arithmetic mean (standard deviation)
    		 7.7 ± 3.7 8.2 ± 3.4 5.6 ± 1 7.3 ± 2.3 6.1 ± 0.9 8.1 ± 3.5 6.8 ± 2.8 -
    Mean screening menstrual blood loss
    Units: mL
        arithmetic mean (standard deviation)
    		 158.3 ± 134.4 161.9 ± 88.2 111 ± 45.5 162.1 ± 83.3 104.5 ± 35.6 162.1 ± 125 159.8 ± 71.7 -
    No. years since last pregnancy
    Units: Years
        arithmetic mean (standard deviation)
    		 8.3 ± 5.3 13.5 ± 7.3 8.9 ± 6.5 8.6 ± 7.4 15.2 ± 6.1 12.1 ± 5.2 14 ± 8.4 -

    End points

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    End points reporting groups
    Reporting group title
    placebo
    Reporting group description
    		 placebo capsule taken orally, twice daily over 5 days.

    Reporting group title
    Dexamethasone 0.4mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.4mg

    Reporting group title
    Dexamethasone 0.8mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose is 0.8mg

    Reporting group title
    Dexamethasone 1.0mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days: total daily dose is 1.0mg

    Reporting group title
    Dexamethasone 1.2mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.2mg

    Reporting group title
    Dexamethasone 1.5mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.5mg

    Reporting group title
    Dexamethasone 1.8mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total daily dose 1.8mg

    Primary: Bayesian analysis of change in mean MBL: Dex 0.4mg

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    End point title
    		 Bayesian analysis of change in mean MBL: Dex 0.4mg [1]
    End point description
    Note: The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Primary
    End point timeframe
    Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 0.4mg
    Number of subjects analysed
    24
    5
    Units: mL
        arithmetic mean (standard deviation)
    -6.0 ± 51.3
    -7.8 ± 54.3
    Statistical analysis title
    		 Bayesian analysis of change in mean MBL: Dex 0.4mg
    Statistical analysis description
    The dose-response curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying dose-response curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).
    Comparison groups
    Dexamethasone 0.4mg v placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28
         upper limit
    		 23
    Variability estimate
    Standard deviation
    Dispersion value
    12.11
    Notes
    [2] - As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals' - and not Confidence intervals.

    Primary: Bayesian analysis of change in mean MBL: Dex 0.8mg

    		 Close Top of page
    End point title
    		 Bayesian analysis of change in mean MBL: Dex 0.8mg [3]
    End point description
    Note: The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Primary
    End point timeframe
    Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 0.8mg
    Number of subjects analysed
    24
    9
    Units: mL
        arithmetic mean (standard deviation)
    -6.0 ± 51.3
    -23.8 ± 41.7
    Statistical analysis title
    		 Bayesian analysis of change in mean MBL: Dex 0.4mg
    Statistical analysis description
    The dose-response curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying dose-response curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).
    Comparison groups
    placebo v Dexamethasone 0.8mg
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41
         upper limit
    		 9
    Variability estimate
    Standard deviation
    Dispersion value
    12.75
    Notes
    [4] - As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals' - and not Confidence intervals.

    Primary: Bayesian analysis of change in mean MBL: Dex 1.0mg

    		 Close Top of page
    End point title
    		 Bayesian analysis of change in mean MBL: Dex 1.0mg [5]
    End point description
    The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Primary
    End point timeframe
    Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 1.0mg
    Number of subjects analysed
    24
    21
    Units: mL
        arithmetic mean (standard deviation)
    -6.0 ± 51.3
    -18.5 ± 37.8
    Statistical analysis title
    		 Bayesian analysis of change in mean MBL: Dex 1.0mg
    Statistical analysis description
    The dose-response curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying dose-response curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).
    Comparison groups
    placebo v Dexamethasone 1.0mg
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29
         upper limit
    		 13
    Variability estimate
    Standard deviation
    Dispersion value
    10.43
    Notes
    [6] - As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals' - and not Confidence intervals.

    Primary: Bayesian analysis of change in mean MBL: Dex 1.2mg

    		 Close Top of page
    End point title
    		 Bayesian analysis of change in mean MBL: Dex 1.2mg [7]
    End point description
    The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Primary
    End point timeframe
    Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 1.2mg
    Number of subjects analysed
    24
    8
    Units: mL
        arithmetic mean (standard deviation)
    -6.0 ± 51.3
    5.8 ± 50.6
    Statistical analysis title
    		 Bayesian analysis of change in mean MBL: Dex 1.2mg
    Statistical analysis description
    The dose-response curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying dose-response curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).
    Comparison groups
    placebo v Dexamethasone 1.2mg
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28
         upper limit
    		 24
    Variability estimate
    Standard deviation
    Dispersion value
    13.19
    Notes
    [8] - As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals' - and not Confidence intervals.

    Primary: Bayesian analysis of change in mean MBL: Dex 1.5mg

    		 Close Top of page
    End point title
    		 Bayesian analysis of change in mean MBL: Dex 1.5mg [9]
    End point description
    The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Primary
    End point timeframe
    Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 1.5mg
    Number of subjects analysed
    24
    14
    Units: mL
        arithmetic mean (standard deviation)
    -6.0 ± 51.3
    -24.5 ± 31.5
    Statistical analysis title
    		 Bayesian analysis of change in mean MBL: Dex 0.4mg
    Statistical analysis description
    The dose-response curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying dose-response curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).
    Comparison groups
    placebo v Dexamethasone 1.5mg
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37
         upper limit
    		 8
    Variability estimate
    Standard deviation
    Dispersion value
    11.53
    Notes
    [10] - As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals' - and not Confidence intervals.

    Primary: Bayesian analysis of change in mean MBL: Dex 1.8mg

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    End point title
    		 Bayesian analysis of change in mean MBL: Dex 1.8mg [11]
    End point description
    The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Primary
    End point timeframe
    Change in MBL between screening (mean of screening cycles 1 and 2) and mean of treatment cycles 2 and 3 (of 3) : average time period was 5 months
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 1.8mg
    Number of subjects analysed
    24
    16
    Units: mL
        arithmetic mean (standard deviation)
    -6.0 ± 51.3
    -36.7 ± 53.8
    Statistical analysis title
    		 Bayesian analysis of change in mean MBL: Dex 1.8mg
    Statistical analysis description
    The dose-response curve for the primary outcome was analysed using a Bayesian second order normal dynamic linear model (NDLM), which is flexible and requires few assumptions about the shape of the underlying dose-response curve. The model adjusted for the screening MBL measurements of each woman. For each Dexamethasone dose, a 95% credible interval was then calculated for the mean difference in MBL change (Dexamethasone minus placebo).
    Comparison groups
    placebo v Dexamethasone 1.8mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49
         upper limit
    		 -1
    Variability estimate
    Standard deviation
    Dispersion value
    12.21
    Notes
    [12] - As we used Bayesian analysis the precision/dispersion type is actually 95% 'Credible Intervals' - and not Confidence intervals.

    Secondary: Change from screening in diary-assessed volume of MBL:Dex 0.4mg

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    End point title
    		 Change from screening in diary-assessed volume of MBL:Dex 0.4mg [13]
    End point description
    The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume. The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Secondary
    End point timeframe
    Two screening menstrual cycles to 3 treatment cycles: average time period was 5 months
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 0.4mg
    Number of subjects analysed
    25
    5
    Units: mL
        arithmetic mean (standard deviation)
    6.9 ± 102.0
    -13.1 ± 58.6
    Statistical analysis title
    		 Bayesian analysis:change in mean MBL- diary score
    Statistical analysis description
    Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diary-assessed volume of menstrual blood loss. The analysis calculates median difference and 95% 'Credible intervals' - so not Confidence intervals
    Comparison groups
    Dexamethasone 0.4mg v placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -59
         upper limit
    		 23
    Variability estimate
    Standard deviation
    Dispersion value
    20.51
    Notes
    [14] - As we used Bayesian analysis the precision/dispersion is actually 95% 'Credible Intervals' - and not Confidence intervals.

    Secondary: Change from screening in diary-assessed volume of MBL:Dex 0.8mg

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    End point title
    		 Change from screening in diary-assessed volume of MBL:Dex 0.8mg [15]
    End point description
    The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume. The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Secondary
    End point timeframe
    Two screening menstrual cycles to 3 treatment cycles - average time period is 5 months
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 0.8mg
    Number of subjects analysed
    25
    9
    Units: mL
        arithmetic mean (standard deviation)
    6.9 ± 102.0
    -40.5 ± 65.4
    Statistical analysis title
    		 Bayesian analysis:change in mean MBL- diary score
    Statistical analysis description
    Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diary-assessed volume of menstrual blood loss. The analysis calculates median difference and 95% 'Credible intervals' - so not Confidence intervals
    Comparison groups
    placebo v Dexamethasone 0.8mg
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -30
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -76
         upper limit
    		 7
    Variability estimate
    Standard deviation
    Dispersion value
    21.58
    Notes
    [16] - The analysis calculates median difference and 95% 'Credible intervals' - so not Confidence intervals

    Secondary: Change from screening in diary-assessed volume of MBL:Dex 1.0mg

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    End point title
    		 Change from screening in diary-assessed volume of MBL:Dex 1.0mg [17]
    End point description
    The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume. The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Secondary
    End point timeframe
    Two screening menstrual cycles to 3 treatment cycles - average time period is 5 months
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 1.0mg
    Number of subjects analysed
    25
    21
    Units: mL
        arithmetic mean (standard deviation)
    6.9 ± 102.0
    0.1 ± 55.4
    Statistical analysis title
    		 Bayesian analysis:change in mean MBL- diary score
    Statistical analysis description
    Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diary-assessed volume of menstrual blood loss. The analysis calculates median difference and 95% 'Credible intervals' - so not Confidence intervals
    Comparison groups
    placebo v Dexamethasone 1.0mg
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40
         upper limit
    		 24
    Variability estimate
    Standard deviation
    Dispersion value
    16.17
    Notes
    [18] - The analysis calculates median difference and 95% 'Credible intervals' - so not Confidence intervals

    Secondary: Change from screening in diary-assessed volume of MBL:Dex 1.2mg

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    End point title
    		 Change from screening in diary-assessed volume of MBL:Dex 1.2mg [19]
    End point description
    The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume. The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Secondary
    End point timeframe
    Two screening menstrual cycles to 3 treatment cycles - average time period is 5 months
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 1.2mg
    Number of subjects analysed
    25
    8
    Units: mL
        arithmetic mean (standard deviation)
    6.9 ± 102.0
    7.2 ± 23.3
    Statistical analysis title
    		 Bayesian analysis:change in mean MBL- diary score
    Statistical analysis description
    Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diary-assessed volume of menstrual blood loss. The analysis calculates median difference and 95% 'Credible intervals' - so not Confidence intervals
    Comparison groups
    placebo v Dexamethasone 1.2mg
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41
         upper limit
    		 36
    Variability estimate
    Standard deviation
    Dispersion value
    19.85
    Notes
    [20] - The analysis calculates median difference and 95% 'Credible intervals' - so not Confidence intervals

    Secondary: Change from screening in diary-assessed volume of MBL:Dex 1.5mg

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    End point title
    		 Change from screening in diary-assessed volume of MBL:Dex 1.5mg [21]
    End point description
    The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume. The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Secondary
    End point timeframe
    Two screening menstrual cycles to 3 treatment cycles - average time period is 5 months
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 1.5mg
    Number of subjects analysed
    25
    15
    Units: mL
        arithmetic mean (standard deviation)
    6.9 ± 102.0
    -0.9 ± 51.9
    Statistical analysis title
    		 Bayesian analysis:change in mean MBL- diary score
    Statistical analysis description
    Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diary-assessed volume of menstrual blood loss. The analysis calculates median difference and 95% 'Credible intervals' - so not Confidence intervals
    Comparison groups
    placebo v Dexamethasone 1.5mg
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44
         upper limit
    		 26
    Variability estimate
    Standard deviation
    Dispersion value
    17.4
    Notes
    [22] - The analysis calculates median difference and 95% 'Credible intervals' - so not Confidence intervals

    Secondary: Change from screening in diary-assessed volume of MBL:Dex 1.8mg

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    End point title
    		 Change from screening in diary-assessed volume of MBL:Dex 1.8mg [23]
    End point description
    The menstrual diary score (MDS) was calculated based on the method of scoring shown in Wyatt et al. (2001) using the patient responses to the menstrual chart in the patient study diary. The derived scores were calculated for each period day and then summed across all period days for each screening/treatment cycle. The difference in mean MDS between the treatment and screening phases was then calculated. The MDS is used to estimate the difference in menstrual period volume. The comparison groups are each of the Dexamethasone doses versus placebo. So we report an endpoint for the comparison of each Dexamethasone dose versus placebo.
    End point type
    Secondary
    End point timeframe
    Two screening menstrual cycles to 3 treatment cycles - average time period is 5 months
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The design used is a response-adaptive, double blind, parallel group, dose finding randomised controlled trial. A Bayesian approach was used to compare 6 doses of Dexamethasone to placebo. In order to fit our analyses with the EudraCT reporting system options we have to create endpoints for each comparison (eg 0.4mg Dexamethasone to placebo) and therefore cannot include all treatment arms within a single endpoint entry.
    End point values
    		 placebo Dexamethasone 1.8mg
    Number of subjects analysed
    25
    16
    Units: mL
        arithmetic mean (standard deviation)
    6.9 ± 102.0
    -29.5 ± 59.5
    Statistical analysis title
    		 Bayesian analysis:change in mean MBL- diary score
    Statistical analysis description
    Bayesian analysis: A normal dynamic linear model was used to calculate the posterior median difference between each Dexamethasone dose and placebo according to the mean change from screening in diary-assessed volume of menstrual blood loss. The analysis calculates median difference and 95% 'Credible intervals' - so not Confidence intervals
    Comparison groups
    placebo v Dexamethasone 1.8mg
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    Method
    Parameter type
    		 Treatment contrast
    Point estimate
    -32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -69
         upper limit
    		 4
    Variability estimate
    Standard deviation
    Dispersion value
    18.56
    Notes
    [24] - The analysis calculates median difference and 95% 'Credible intervals' - so not Confidence intervals

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Consent to final follow-up visit (approx 30 days after day of last treatment)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    placebo
    Reporting group description
    		 placebo

    Reporting group title
    Dexamethasone 0.4mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total dose is 0.4mg

    Reporting group title
    Dexamethasone 0.8mg
    Reporting group description
    		 Dexamethasone taken orally twice daily over 5 days. Total dose is 0.8mg

    Reporting group title
    Dexamethasone 1.0mg
    Reporting group description
    		 Dexamethasone taken orally twice daily total dose is 1.0mg

    Reporting group title
    Dexamethasone 1.2mg
    Reporting group description
    		 Dexamethasone taken orally twice daily total dose 1.2mg

    Reporting group title
    Dexamethasone 1.5mg
    Reporting group description
    		 Dexamethasone taken orally twice daily total dose 1.5mg

    Reporting group title
    Dexamethasone 1.8mg
    Reporting group description
    		 Dexamethasone taken orally twice daily. Total dose 1.8mg

    Serious adverse events
    		 placebo Dexamethasone 0.4mg Dexamethasone 0.8mg Dexamethasone 1.0mg Dexamethasone 1.2mg Dexamethasone 1.5mg Dexamethasone 1.8mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    trapped sciatic nerve
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 placebo Dexamethasone 0.4mg Dexamethasone 0.8mg Dexamethasone 1.0mg Dexamethasone 1.2mg Dexamethasone 1.5mg Dexamethasone 1.8mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 26 (61.54%)
    5 / 6 (83.33%)
    6 / 9 (66.67%)
    17 / 21 (80.95%)
    6 / 9 (66.67%)
    11 / 15 (73.33%)
    13 / 17 (76.47%)
    Vascular disorders
    vasomotor
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Surgical and medical procedures
    Surgery
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
    2 / 17 (11.76%)
         occurrences all number
    1
    0
    2
    0
    0
    3
    2
    increased energy
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Menstrual discomfort
         subjects affected / exposed
    5 / 26 (19.23%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    3 / 21 (14.29%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
    1 / 17 (5.88%)
         occurrences all number
    7
    0
    0
    4
    1
    1
    1
    Vaginal discharge
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 6 (16.67%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    1
    0
    Infection
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    1
    1
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory symptom
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    2 / 15 (13.33%)
    3 / 17 (17.65%)
         occurrences all number
    2
    1
    1
    1
    1
    3
    3
    disturbed sleep
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    4
    Investigations
    Colposcopy
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Infected bite
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Fracture
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Musculoskeletal injury
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    5 / 21 (23.81%)
    2 / 9 (22.22%)
    1 / 15 (6.67%)
    1 / 17 (5.88%)
         occurrences all number
    3
    0
    0
    6
    2
    1
    1
    Fatigue
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
    5 / 17 (29.41%)
         occurrences all number
    3
    0
    1
    0
    0
    3
    9
    Sciatica
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    swollen neck glands
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    ear wax
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    5 / 21 (23.81%)
    1 / 9 (11.11%)
    3 / 15 (20.00%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    1
    6
    2
    4
    2
    Abdominal distension
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    2
    0
    1
    2
    0
    0
    2
    gastrointestinal disturbance
         subjects affected / exposed
    1 / 26 (3.85%)
    4 / 6 (66.67%)
    1 / 9 (11.11%)
    8 / 21 (38.10%)
    2 / 9 (22.22%)
    5 / 15 (33.33%)
    4 / 17 (23.53%)
         occurrences all number
    3
    4
    1
    10
    3
    7
    6
    Skin and subcutaneous tissue disorders
    Dermatosis
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 6 (16.67%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    2 / 15 (13.33%)
    1 / 17 (5.88%)
         occurrences all number
    2
    2
    1
    1
    1
    2
    1
    vasomotor
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Renal and urinary disorders
    urinary frequency
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    3 / 15 (20.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    2
    0
    3
    1
    joint fusion
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Infection
         subjects affected / exposed
    4 / 26 (15.38%)
    2 / 6 (33.33%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
    2 / 9 (22.22%)
    3 / 15 (20.00%)
    5 / 17 (29.41%)
         occurrences all number
    5
    2
    0
    4
    3
    6
    6
    Viral infection
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
    2 / 17 (11.76%)
         occurrences all number
    2
    0
    1
    1
    0
    1
    2
    Fungal infection
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Blood glucose fluctuation
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Increased appetite
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Feb 2013
    Protocol wording clarification for workup studies: describe randomisation process, add NIMP for study 1, process for AE recording
    22 Oct 2013
    Protocol wording clarification for: Inclusion/exclusion criteria, study procedures
    19 Feb 2014
    Protocol wording clarification for adaptive trial; update processes for adaptive trial using experience from the completed work-up studies. Extension to recruitment period and approaches. New study materials.
    18 Dec 2014
    Protocol wording clarification; addition of new recruitment approach; New SmPC for Dexamethasone
    23 May 2016
    Extension to recruitment period; details for additional recruitment approach .
    19 Oct 2017
    Changes to RSI in SmPC for Dexamethasone.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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