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    Clinical Trial Results:
    A Phase III study of efficacy, safety and tolerability of Chronocort® compared with standard glucocorticoid replacement therapy in the treatment of congenital adrenal hyperplasia.

    Summary
    EudraCT number
    2015-000711-40
    Trial protocol
    GB   DE   SE   NL   DK  
    Global end of trial date
    28 Jul 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jul 2019
    First version publication date
    26 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DIUR-005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02716818
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Diurnal Ltd
    Sponsor organisation address
    Cardiff Medicentre, Cardiff, United Kingdom, CF14 4UJ
    Public contact
    Clinical Trials Information, Diurnal Ltd, info@diurnal.co.uk
    Scientific contact
    Clinical Trials Information, Diurnal Ltd, info@diurnal.co.uk
    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
    28 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superior efficacy of Chronocort compared with standard glucocorticoid replacement therapy in the treatment of congenital adrenal hyperplasia (CAH). This will be assessed by establishing whether Chronocort can provide improved control of serum androgen levels compared to current glucocorticoid treatment regimens.
    Protection of trial subjects
    The principles of informed consent in the Declaration of Helsinki, in the current requirements of Good Clinical Practice, (published by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) and local regulation, whichever afforded the greater participant protection, were implemented before any protocol-specified procedures or interventions were carried out. At Dutch centres only, potential participants were approached by their own treating physician. If the treating physician was also the study Investigator, the participant information sheet was provided immediately. If this was not the case, then the treating physician asked the participant for permission for the Investigator to approach them about study participation. All data computer-processed by Diurnal Ltd. was identified by participant number/study code. Extra precautions were taken to preserve confidentiality and prevent genetic information being linked to the identity of the participant. This involved coding of the samples and data. For coded samples this meant that there was segregation of the databases containing coded genotypic and clinical information, with protection of confidentiality achieved by limited access.
    Background therapy
    Fludrocortisone was prescribed to patients with the salt-wasting form of CAH.
    Evidence for comparator
    The comparator used in this trial was standard glucocorticoid therapy, according to the patient's normal standard of care. Standard glucocorticoid therapy consists of hydrocortisone, prednisone, prednisolone and/or dexamethasone, or any combination of the aforementioned drugs.
    Actual start date of recruitment
    30 Sep 2015
    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
    Netherlands: 15
    Country: Number of subjects enrolled
    Sweden: 20
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    138
    EEA total number of subjects
    130
    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)
    136
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 11 study sites in 7 countries: Denmark 1, France 2, Germany 1, Netherlands 1, Sweden 1, UK 4, and USA 1.

    Pre-assignment
    Screening details
    Following written informed consent and screening tests (Visit 0), eligible participants were called back for the baseline visit. As part of the baseline assessment, participants were admitted overnight for a 24-hour endocrine profile whilst remaining on their standard GC therapy. Participants were then randomised to Chronocort or standard therapy.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Chronocort
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Chronocort
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients randomised to the Chronocort arm were provided a total daily dose that was equivalent to their previous daily dose of standard glucocorticoid therapy, up to a maximum of 30mg per day.

    Arm title
    Standard Glucocorticoid Therapy
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Hydrocortisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients randomised to the standard glucocorticoid therapy arm continued taking the same dose that they had taken prior to study participation.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients randomised to the standard glucocorticoid therapy arm continued taking the same dose that they had taken prior to study participation.

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients randomised to the standard glucocorticoid therapy arm continued taking the same dose that they had taken prior to study participation.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients randomised to the standard glucocorticoid therapy arm continued taking the same dose that they had taken prior to study participation.

    Number of subjects in period 1 [1]
    Chronocort Standard Glucocorticoid Therapy
    Started
    61
    61
    Completed
    58
    59
    Not completed
    3
    2
         Physician decision
    -
    1
         Adverse event, non-fatal
    1
    -
         Consent withdrawn by subject
    2
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: There are 122 subjects overall reported in the baseline period (61 in Chronocort arm, 61 in standard GC therapy). The number of subjects entering the treatment period is the same as this, but the number of "Completed" subjects is lower due to dropouts.

    Baseline characteristics

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

    Reporting group title
    Standard Glucocorticoid Therapy
    Reporting group description
    -

    Reporting group values
    Chronocort Standard Glucocorticoid Therapy Total
    Number of subjects
    61 61 122
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    61 59 120
        From 65-84 years
    0 2 2
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    42 36 78
        Male
    19 25 44

    End points

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

    Reporting group title
    Standard Glucocorticoid Therapy
    Reporting group description
    -

    Subject analysis set title
    Pre-Baseline - Hydrocortisone - 17-OHP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of 17-OHP (17-Hydroxyprogesterone) by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).

    Subject analysis set title
    Pre-Baseline - Prednisone/Prednisolone - 17-OHP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).

    Subject analysis set title
    Pre-Baseline - Dexamethasone - 17-OHP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).

    Subject analysis set title
    Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set).

    Subject analysis set title
    Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)

    Subject analysis set title
    Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of 17-OHP by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)

    Subject analysis set title
    Pre-Baseline - Hydrocortisone - Androstenedione (A4)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)

    Subject analysis set title
    Pre-Baseline - Prednisone/Prednisolone - A4
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)

    Subject analysis set title
    Pre-Baseline - Dexamethasone - A4
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)

    Subject analysis set title
    Pre-Baseline - Chronocort vs. Hydrocortisone - A4
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)

    Subject analysis set title
    Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)

    Subject analysis set title
    Pre-Baseline - Chronocort vs. Dexamethasone - A4
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of A4 by pre-treatment strata, change from baseline to 24 weeks in primary efficacy variable, analysis of covariance model (Efficacy evaluable analysis set)

    Subject analysis set title
    Chronocort - 09:00h response - 17-OHP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    A subject will be considered a responder if their 09:00h results at week 24 are in the optimal range for 17-OHP.

    Subject analysis set title
    Chronocort - 09:00h response - A4
    Subject analysis set type
    Per protocol
    Subject analysis set description
    A subject will be considered a responder if their 09:00h results at week 24 are in the optimal range for A4.

    Subject analysis set title
    Standard GC Therapy - 09:00h response - 17-OHP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    A subject will be considered a responder if their 09:00h results at week 24 are in the optimal range for 17-OHP.

    Subject analysis set title
    Standard GC Therapy - 09:00h response - A4
    Subject analysis set type
    Per protocol
    Subject analysis set description
    A subject will be considered a responder if their 09:00h results at week 24 are in the optimal range for A4.

    Subject analysis set title
    Chronocort - DEXA - Fat Mass
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of change from baseline to 24 weeks in body composition (fat mass) - Dual Energy X-ray Absorptiometry (DEXA), analysis of covariance model (Efficacy evaluable analysis set)

    Subject analysis set title
    Standard GC Therapy - DEXA - Fat Mass
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of change from baseline to 24 weeks in body composition - DEXA; analysis of covariance model (Efficacy evaluable analysis set).

    Subject analysis set title
    Chronocort - DEXA - Lean Mass
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of change from baseline to 24 weeks in body composition - DEXA; analysis of covariance model (Efficacy evaluable analysis set).

    Subject analysis set title
    Standard GC Therapy - DEXA - Lean Mass
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of change from baseline to 24 weeks in body composition - DEXA; analysis of covariance model (Efficacy evaluable analysis set).

    Subject analysis set title
    Chronocort - DEXA - Bone Mineral Density
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of change from baseline to 24 weeks in body composition - DEXA; analysis of covariance model (Efficacy evaluable analysis set).

    Subject analysis set title
    Standard GC Therapy - DEXA - Bone Mineral Density
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Secondary efficacy analysis of change from baseline to 24 weeks in body composition - DEXA; analysis of covariance model (Efficacy evaluable analysis set).

    Primary: Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) profile for 17-OHP

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    End point title
    Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) profile for 17-OHP
    End point description
    The primary efficacy endpoint was the change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) profile for 17-OHP (efficacy evaluable analysis set). The SDS profile was calculated as the SDS of log transformed 17-OHP concentration unsigned. A negative value indicates better hormonal control versus baseline, and a difference in LS means < 0 favours Chronocort.
    End point type
    Primary
    End point timeframe
    24 weeks.
    End point values
    Chronocort Standard Glucocorticoid Therapy
    Number of subjects analysed
    53
    52
    Units: N/A - SDS
        arithmetic mean (standard deviation)
    -0.403 ± 0.8499
    -0.172 ± 0.7776
    Statistical analysis title
    Primary efficacy analysis for 17-OHP
    Statistical analysis description
    The primary efficacy variable was the natural logarithm of the mean of the 24-hour SDS profile for the natural logarithm of 17-OHP. The SDS profile was calculated as the SDS of log transformed 17-OHP concentration unsigned. The mean of the 24-hour SDS profile for each visit was the arithmetic mean of all the SDSs, with the first and last (13th) weighted one half relative to the intermediate SDSs.
    Comparison groups
    Chronocort v Standard Glucocorticoid Therapy
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5521
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.069
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.299
         upper limit
    0.161

    Secondary: Change from baseline to 24 weeks of the mean of the 24-hour SDS profile for A4.

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    End point title
    Change from baseline to 24 weeks of the mean of the 24-hour SDS profile for A4.
    End point description
    The change from baseline to 24 weeks of the mean of the 24-hour SDS profile for A4 (calculated in the same way as the primary endpoint).
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Chronocort Standard Glucocorticoid Therapy
    Number of subjects analysed
    53
    52
    Units: N/A - SDS
        arithmetic mean (standard deviation)
    0.113 ± 0.9221
    -0.041 ± 0.7731
    Statistical analysis title
    Change from Baseline to 24 Weeks in A4
    Statistical analysis description
    Change from Baseline to 24 Weeks in A4 Using an ANCOVA Model - The analysis conducted for the primary endpoint variable analysis of 17-OHP was repeated for A4.
    Comparison groups
    Standard Glucocorticoid Therapy v Chronocort
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7405
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.234
         upper limit
    0.329

    Secondary: 17-OHP and A4 by individual baseline treatment strata

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    End point title
    17-OHP and A4 by individual baseline treatment strata
    End point description
    17-OHP and A4 by individual baseline treatment strata presented in the same manner as the primary endpoint (using 24-hour SDS profile at 24 weeks).
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Pre-Baseline - Hydrocortisone - 17-OHP Pre-Baseline - Prednisone/Prednisolone - 17-OHP Pre-Baseline - Dexamethasone - 17-OHP Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP Pre-Baseline - Hydrocortisone - Androstenedione (A4) Pre-Baseline - Prednisone/Prednisolone - A4 Pre-Baseline - Dexamethasone - A4 Pre-Baseline - Chronocort vs. Hydrocortisone - A4 Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4 Pre-Baseline - Chronocort vs. Dexamethasone - A4
    Number of subjects analysed
    27
    21
    4
    31
    18
    4
    27
    21
    4
    31
    18
    4
    Units: N/A - SDS
        arithmetic mean (standard deviation)
    -0.248 ± 0.7661
    -0.061 ± 0.8051
    -0.245 ± 0.8522
    -0.431 ± 0.8727
    -0.320 ± 0.7627
    -0.565 ± 1.2343
    -0.211 ± 0.7426
    0.100 ± 0.8339
    0.368 ± 0.3521
    0.015 ± 1.0128
    0.328 ± 0.7256
    -0.092 ± 1.0310
    Statistical analysis title
    Chronocort vs. Hydrocortisone - 17-OHP
    Comparison groups
    Pre-Baseline - Hydrocortisone - 17-OHP v Pre-Baseline - Chronocort vs. Hydrocortisone - 17-OHP
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8186
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.037
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.354
         upper limit
    0.281
    Statistical analysis title
    Chronocort vs. Prednisone/Prednisolone - 17-OHP
    Comparison groups
    Pre-Baseline - Prednisone/Prednisolone - 17-OHP v Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - 17-OHP
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4655
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.135
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.508
         upper limit
    0.237
    Statistical analysis title
    Chronocort vs. Dexamethasone - 17-OHP
    Comparison groups
    Pre-Baseline - Dexamethasone - 17-OHP v Pre-Baseline - Chronocort vs. Dexamethasone - 17-OHP
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9081
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.32
         upper limit
    1.451
    Statistical analysis title
    Chronocort vs. Hydrocortisone - A4
    Comparison groups
    Pre-Baseline - Hydrocortisone - Androstenedione (A4) v Pre-Baseline - Chronocort vs. Hydrocortisone - A4
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6729
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.092
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.343
         upper limit
    0.527
    Statistical analysis title
    Chronocort vs. Prednisone/Prednisolone - A4
    Comparison groups
    Pre-Baseline - Prednisone/Prednisolone - A4 v Pre-Baseline - Chronocort vs. Prednisone/Prednisolone - A4
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5322
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.116
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.257
         upper limit
    0.489
    Statistical analysis title
    Chronocort vs. Dexamethasone - A4
    Comparison groups
    Pre-Baseline - Dexamethasone - A4 v Pre-Baseline - Chronocort vs. Dexamethasone - A4
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2885
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.568
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.799
         upper limit
    0.662

    Secondary: 17-OHP and A4 levels at 09:00 as a responder analysis

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    End point title
    17-OHP and A4 levels at 09:00 as a responder analysis
    End point description
    17-OHP and A4 levels at 09:00 as a responder analysis (i.e. the number of participants achieving results in the optimal range).
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Chronocort - 09:00h response - 17-OHP Chronocort - 09:00h response - A4 Standard GC Therapy - 09:00h response - 17-OHP Standard GC Therapy - 09:00h response - A4
    Number of subjects analysed
    53
    53
    52
    52
    Units: Number of subjects with a response
    30
    25
    30
    30
    Statistical analysis title
    Responders at 09:00 - 17-OHP
    Comparison groups
    Chronocort - 09:00h response - 17-OHP v Standard GC Therapy - 09:00h response - 17-OHP
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9877
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    2.19
    Statistical analysis title
    Responders at 09:00 - A4
    Comparison groups
    Chronocort - 09:00h response - A4 v Standard GC Therapy - 09:00h response - A4
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8498
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    2.02

    Secondary: Changes relative to standard GC therapy in body composition (DEXA) (fat mass, lean mass) - measured at all sites except Germany.

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    End point title
    Changes relative to standard GC therapy in body composition (DEXA) (fat mass, lean mass) - measured at all sites except Germany.
    End point description
    Changes relative to standard GC therapy in body composition (DEXA) (fat mass and lean mass) - measured at all sites except Germany.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Chronocort - DEXA - Fat Mass Standard GC Therapy - DEXA - Fat Mass Chronocort - DEXA - Lean Mass Standard GC Therapy - DEXA - Lean Mass
    Number of subjects analysed
    43
    39
    43
    39
    Units: kilograms
        arithmetic mean (standard deviation)
    -0.575 ± 3.2744
    0.445 ± 2.4660
    0.640 ± 2.3304
    0.234 ± 1.3689
    Statistical analysis title
    Change in Fat Mass - Chronocort vs. Standard GC
    Statistical analysis description
    German subjects have been excluded from this analysis as DEXA scans were not performed at the German site.
    Comparison groups
    Chronocort - DEXA - Fat Mass v Standard GC Therapy - DEXA - Fat Mass
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.156
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.294
         upper limit
    0.374
    Statistical analysis title
    Change in Lean Mass - Chronocort vs. Standard GC
    Statistical analysis description
    German subjects have been excluded from this analysis as DEXA scans were not performed at the German site.
    Comparison groups
    Chronocort - DEXA - Lean Mass v Standard GC Therapy - DEXA - Lean Mass
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3392
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.425
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.455
         upper limit
    1.305

    Secondary: Changes relative to standard GC therapy in body composition (DEXA) (bone mineral density) - measured at all sites except Germany.

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    End point title
    Changes relative to standard GC therapy in body composition (DEXA) (bone mineral density) - measured at all sites except Germany.
    End point description
    Secondary efficacy analysis of change from baseline to 24 weeks in body composition (DEXA), analysis of covariance model (Efficacy evaluable analysis set)
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Chronocort - DEXA - Bone Mineral Density Standard GC Therapy - DEXA - Bone Mineral Density
    Number of subjects analysed
    35
    36
    Units: g/cm2
        arithmetic mean (standard deviation)
    -0.001 ± 0.0250
    -0.008 ± 0.0399
    Statistical analysis title
    Change in Bone Mineral Density - Chronocort vs GC
    Statistical analysis description
    German subjects have been excluded from the analysis as DEXA scans are not performed at German sites.
    Comparison groups
    Chronocort - DEXA - Bone Mineral Density v Standard GC Therapy - DEXA - Bone Mineral Density
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2614
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.009
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.007
         upper limit
    0.025

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from enrolment to study completion (24 weeks).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Chronocort
    Reporting group description
    -

    Reporting group title
    Standard Glucocorticoid Therapy
    Reporting group description
    -

    Serious adverse events
    Chronocort Standard Glucocorticoid Therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 61 (11.48%)
    5 / 61 (8.20%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Odema Peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal Insufficiency
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Andrenocortical Insufficiency Acute
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Viral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsilitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Chronocort Standard Glucocorticoid Therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 61 (96.72%)
    48 / 61 (78.69%)
    Vascular disorders
    Haematoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Hypertension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Hypotension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Pallor
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 61 (4.92%)
         occurrences all number
    6
    3
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Fat tissue increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 61 (14.75%)
    10 / 61 (16.39%)
         occurrences all number
    13
    20
    Inflammation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    4 / 61 (6.56%)
         occurrences all number
    3
    4
    Malaise
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 61 (8.20%)
    2 / 61 (3.28%)
         occurrences all number
    5
    2
    Oedema peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    3
    Peripheral swelling
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 61 (14.75%)
    4 / 61 (6.56%)
         occurrences all number
    9
    4
    Sensation of foreign body
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Therapeutic response unexpected
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 61 (16.39%)
    1 / 61 (1.64%)
         occurrences all number
    15
    1
    Thirst
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Affect lability
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Agitation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    3
    Anxiety
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Burnout syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Depressed mood
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 61 (1.64%)
         occurrences all number
    2
    1
    Depression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 61 (3.28%)
         occurrences all number
    3
    2
    Emotional distress
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Insomnia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 61 (8.20%)
    4 / 61 (6.56%)
         occurrences all number
    6
    4
    Irritability
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Libido decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    Sleep disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    Stress
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 61 (4.92%)
         occurrences all number
    1
    3
    Reproductive system and breast disorders
    Erectile dysfunction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Menstruation irregular
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Auricular haematoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Contusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Ear injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Hand fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Limb injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Procedural complication
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Procedural pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Sunburn
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Toxicity to various agents
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Wound
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Blood glucose increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Blood sodium decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Body temperature increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    C-telopeptide increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Haematocrit decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Haemoglobin decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Liver function test abnormal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Osteocalcin decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Renin increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 61 (4.92%)
    7 / 61 (11.48%)
         occurrences all number
    3
    7
    Urine output decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Weight increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    White blood cell count increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Cardiac disorders
    Palpitations
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 61 (4.92%)
         occurrences all number
    1
    3
    Sinus tachycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Tachycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 61 (4.92%)
         occurrences all number
    4
    3
    Iron deficiency anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 61 (0.00%)
         occurrences all number
    4
    0
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    Nasal congestion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Oropharyngeal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    Rhinorrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    Nervous system disorders
    Carpal tunnel syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Circadian rhythm sleep disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 61 (11.48%)
    4 / 61 (6.56%)
         occurrences all number
    13
    5
    Dizziness postural
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 61 (24.59%)
    15 / 61 (24.59%)
         occurrences all number
    19
    22
    Lethargy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Memory impairment
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Migraine
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences all number
    2
    1
    Paraesthesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 61 (1.64%)
         occurrences all number
    2
    1
    Peripheral nerve lesion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Poor quality sleep
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Psychomotor hyperactivity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Sensory loss
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Somnolence
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    Syncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Tension headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    0
    2
    Tremor
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Eye disorders
    Chalazion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Foreign body sensation in eyes
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Lacrimation increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 61 (1.64%)
         occurrences all number
    3
    1
    Ear and labyrinth disorders
    Ear deformity acquired
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    2
    Ear pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Tympanic membrane perforation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Vertigo
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Vertigo positional
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 61 (3.28%)
         occurrences all number
    2
    3
    Abdominal pain lower
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Abdominal pain upper
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 61 (0.00%)
         occurrences all number
    7
    0
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Dental caries
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 61 (4.92%)
         occurrences all number
    6
    3
    Diverticulum intestinal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Dyspepsia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Epigastric discomfort
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Faeces soft
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Food poisoning
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Inguinal hernia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 61 (13.11%)
    4 / 61 (6.56%)
         occurrences all number
    9
    5
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 61 (4.92%)
         occurrences all number
    4
    4
    Skin and subcutaneous tissue disorders
    Acne
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Alopecia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Blister
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Chloasma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Cold sweat
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Eczema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    Erythema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Hair growth abnormal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 61 (1.64%)
         occurrences all number
    2
    1
    Psoriasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 61 (0.00%)
         occurrences all number
    3
    0
    Urticaria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 61 (3.28%)
         occurrences all number
    3
    2
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 61 (4.92%)
         occurrences all number
    4
    3
    Joint stiffness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Muscle fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Muscle tightness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    Muscular weakness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 61 (1.64%)
         occurrences all number
    2
    1
    Myalgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    Neck pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Osteoarthritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences all number
    2
    1
    Endocrine disorders
    Mineralocorticoid deficiency
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Abnormal loss of weight
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Abnormal weight gain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 61 (3.28%)
         occurrences all number
    3
    2
    Alcohol intolerance
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Fluid retention
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 61 (3.28%)
         occurrences all number
    1
    2
    Gluten sensitivity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Hyperinsulinaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 61 (1.64%)
         occurrences all number
    3
    1
    Impaired fasting glucose
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 61 (1.64%)
         occurrences all number
    3
    1
    Increased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 61 (8.20%)
    2 / 61 (3.28%)
         occurrences all number
    5
    2
    Weight fluctuation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Acute sinusitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis viral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Cystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea infectious
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Ear infection fungal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 61 (6.56%)
         occurrences all number
    1
    4
    Gastroenteritis viral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    Influenza
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 61 (1.64%)
         occurrences all number
    2
    1
    Lower respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Oral candidiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Otitis media
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Otitis media acute
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Paronychia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Sinusitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 61 (1.64%)
         occurrences all number
    2
    1
    Tonsilitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Tooth infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    3 / 61 (4.92%)
         occurrences all number
    1
    3
    Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 61 (6.56%)
    2 / 61 (3.28%)
         occurrences all number
    4
    2
    Viral infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    1
    0
    Viral rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    Viral upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 61 (19.67%)
    13 / 61 (21.31%)
         occurrences all number
    16
    15
    Salpingitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 61 (0.00%)
         occurrences all number
    2
    0
    Herpes zoster
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Sep 2015
    Protocol v2.0 dated 03 September 2015: The protocol was amended to address MHRA comments on the protocol and to make a small administrative change to the Adrenal Insufficiency Checklist. The following changes were made: 1) Modification of the RSI in the Investigator’s Brochure (IB) necessitated an update to Appendix 3 (Expected Adverse Events) in the protocol. 2) Clarification was added that the DSMB is independent. 3) The inclusion criteria of PRA less than 2 x ULN was reduced to PRA less than 1.5 x ULN. 4) Appendix 5 was updated to a newer version of the Adrenal Insufficiency Checklist (minor administrative change).
    03 Dec 2015
    Protocol v3.0 dated 03 December 2015: The protocol was amended to address the Swedish Medicines Agency and the US National Institutes of Health comments on the protocol that a separate benefit/risk assessment should be added. The following changes were made: 1) Section 5: new section added at the end of Section 5 titled Benefit/Risk Assessment.
    28 May 2016
    Protocol v4.0 dated 28 May 2016: The following changes were made to the protocol: 1) Sponsor signatory changed. 2) Added a maximum possible dose of 30mg hydrocortisone (or equivalent when calculating the dose using conversion factors for other glucocorticoid medications used in the trial; prednisone, prednisolone and dexamethasone). 3) Added a clarification that consent must be taken from the patients in order to access genotyping information for the subject that was taken prior to study involvement. 4) Subjects who routinely work night shifts and so do not sleep during the usual nighttime hours was added to the exclusion criteria. 5) At the request of the Dutch ethics committee, the following sentence has been added to the procedures for the screening visit (Section 11.1.1) and also in Section 11.4 (Informed Consent): At Dutch centres only, potential subjects will be approached by their own treating physician. If the treating physician is also the investigator the subject information sheet can be provided immediately. If this is not the case then the treating physician will ask the patient for permission for the investigator to approach them about study participation. 6) It was noted that the terminology for the independent blinded physician was not consistent throughout the protocol so this was corrected throughout. 7) The text in Section 8 (Study Design) and Section 10.4 (Dose Adjustment) was updated to state ‘No dose adjustments outside of the protocol-defined dose adjustments should be conducted, unless clinical signs and symptoms indicate an immediate need. In such cases the Sponsor’s medical monitor must be contacted (preferably before any dose changes are implemented). Any such unscheduled dose adjustments should be based on clinical symptoms only, with repeated androgen testing discouraged and must be pre-approved by the Sponsor’s medical monitor.’
    23 Sep 2016
    Protocol v5.0 dated 23 September 2016: The following changes were made to the protocol: 1) Sponsor signatory changed. 2) The Chronocort® capsules may now be supplied in either blister packs or bottles. Therefore, Section 10.2.2 (Packaging and Labelling) and Appendix 9 (Labelling) were updated.
    13 Apr 2017
    Protocol v6.0 dated 13 April 2017: The following changes were made to the protocol: 1) The statistician was changed. 2) The sample size was increased from 110 to 120 patients due to a higher level of protocol deviations than originally anticipated. As such, the inevaluability rate has been increased from 7% to 15%. 3) The titration instructions in Section 8 (Dose Adjustment) were modified to provide guidance to state that if the independent blinded physician states that a change to the midday dose is needed but the patient is either receiving Chronocort or is receiving twice daily dosing of standard therapy. In such cases the local investigator is instructed to decide whether to adjust the morning or evening dose, based on their judgement, in addition to any changes already advised for morning and evening doses, thus ensuring that the total change advised is accommodated within the day. 4) The screening period has been extended by 1 week (21 days) to allow extra time for the study site to obtain the results of the screening PRA test. 5) Clarification added to Sections 9.2 and 11.7 and the synopsis that female subjects presenting with oligomenorrhoea or amenorrhoea who are aged ≤55 years of age should be considered potentially fertile and therefore, as well as undergoing pregnancy testing like all other female subjects, will be expected to be using an acceptable method of contraception, as listed in Section 11.7. 6) Some events may occur during the study that represent an improvement in the subject's condition e.g. restoration of menses. To ensure sufficient details of such events are recorded, Section 12.9 has been updated to state that these events will be reported in the same manner as SAEs in order to capture the data in real time, together with additional data, if this should be required. However these events will not be reported to the regulatory authorities as SAEs.

    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.
    A limitation of the pre-defined primary endpoint was that it included an unsigned SDS score over a 24-hour period.
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