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    Clinical Trial Results:
    A Randomized, Double-Blind, Active-Controlled, Phase 3 Study of Chronocort Compared With Immediate-Release Hydrocortisone Replacement Therapy in Participants Aged 16 Years and Over With Congenital Adrenal Hyperplasia

    Summary
    EudraCT number
    		 2021-003668-29
    Trial protocol
    		 FR  
    Global end of trial date
    02 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Aug 2024
    First version publication date
    17 Aug 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DIUR-014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05063994
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Diurnal Limited
    Sponsor organisation address
    Cardiff Medicentre, Heath Park, Cardiff, United Kingdom, CF14 4UJ
    Public contact
    Clinical Trials Information, Diurnal Limited, +44 0 292 068 2069, info@diurnal.co.uk
    Scientific contact
    Clinical Trials Information, Diurnal Limited, +44 0 292 068 2069, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Apr 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Feb 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study is a randomized, double-blind, active-controlled, phase III study of Chronocort® compared with immediate-release hydrocortisone replacement therapy in participants aged 16 years and over with Congenital Adrenal Hyperplasia.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki, the Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, in accordance with ICH GCP requirements, and in accordance with the United States of America (USA) Code of Federal Regulations on Protection of Human Rights (21 CFR 50) (for USA sites only).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 May 2022
    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
    France: 21
    Country: Number of subjects enrolled
    Japan: 9
    Country: Number of subjects enrolled
    United States: 23
    Worldwide total number of subjects
    53
    EEA total number of subjects
    21
    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)
    7
    Adults (18-64 years)
    46
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants received IRHC (Cortef) during the run-in therapy for 4 weeks prior to randomization. Once eligibility for the study was confirmed at the Baseline visit, participants were randomized on a 1:1 basis (Chronocort:Cortef). 55 participants entered the run-in period and 53 were randomized to treatment.

    Pre-assignment period milestones
    Number of subjects started
    		 55 [1]
    Number of subjects completed
    		 53

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Did not meet the inclusion/exclusion criteria: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two participants discontinued prior to randomization.
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Chronocort
    Arm description
    		 Participants received Chronocort at a starting dose of 30 milligrams (mg), with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Chronocort
    Investigational medicinal product code
    Other name
    Hydrocortisone modified-release
    Pharmaceutical forms
    Modified-release capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received dosage and administration as specified in the arm description.

    Arm title
    		 Cortef
    Arm description
    		 Participants received Cortef at a starting dose of 30 mg, with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cortef
    Investigational medicinal product code
    Other name
    Immediate-release hydrocortisone, IRHC
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received dosage and administration as specified in the arm description.

    Number of subjects in period 1
    		Chronocort Cortef
    Started
    25
    28
    Full Analysis Set (FAS) Population
    25
    28
    Completed
    25
    25
    Not completed
    0
    3
         Withdrawal of Consent
    -
    1
         Physician decision
    -
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Chronocort
    Reporting group description
    		 Participants received Chronocort at a starting dose of 30 milligrams (mg), with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding.

    Reporting group title
    Cortef
    Reporting group description
    		 Participants received Cortef at a starting dose of 30 mg, with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding.

    Reporting group values
    		 Chronocort Cortef Total
    Number of subjects
    		 25 28 53
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.7 ( 14.68 ) 31.6 ( 13.02 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 16 16 32
        Male
    		 9 12 21
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 3 5
        Not Hispanic or Latino
    		 15 16 31
        Unknown or Not Reported
    		 8 9 17
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 13 12 25
        Black or African American
    		 1 2 3
        Asian
    		 4 5 9
        Not Reportable
    		 6 6 12
        Unknown
    		 1 3 4
    17-Hydroxyprogesterone (17-OHP) Level
    Units: nanograms (ng)/deciliters (dL)
        arithmetic mean (full range (min-max))
    		 3470.48 (43.5 to 16968.5) 5595.36 (10.0 to 14641.5) -
    Androstenedione (A4) Level
    Analysis Population: Participants in the FAS population who had an A4 assessment at the baseline visit. n = 25 for Chronocort and n = 27 for Cortef.
    Units: ng/dL
        arithmetic mean (full range (min-max))
    		 173.30 (5.0 to 1040.5) 483.09 (5.0 to 2516.5) -

    End points

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    End points reporting groups
    Reporting group title
    Chronocort
    Reporting group description
    		 Participants received Chronocort at a starting dose of 30 milligrams (mg), with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding.

    Reporting group title
    Cortef
    Reporting group description
    		 Participants received Cortef at a starting dose of 30 mg, with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding.

    Primary: Percentage of participants who were biochemical responders at Week 28

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    End point title
    		 Percentage of participants who were biochemical responders at Week 28
    End point description
    Biochemical response was defined as a participant who a) was in biochemical control at the 08:00 assessment and b) was receiving a total daily dose of hydrocortisone of not more than 25 mg if the participant was in biochemical control at baseline or not more than 30 mg if the participant was not in biochemical control at baseline. Biochemical control was defined as both a 17-OHP concentration equal to or below the upper limit for optimal control (1200 ng/dL [36.4 nmol/L]) and an A4 concentration equal to or below the upper limit of the reference range (150 ng/dL [5.2 nmol/L] for men and 200 ng/dL [7.0 nmol/L] for women). Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    25
    28
    Units: percentage of participants
        number (not applicable)
    40.0
    14.3
    Statistical analysis title
    		 Analysis of Biochemical Responders
    Comparison groups
    Chronocort v Cortef
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.0003 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment Difference
    Point estimate
    25.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 48.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.82
    Notes
    [1] - Non-inferiority of Chronocort to Cortef was declared if the 95% CI for the difference in biochemical response rates between the 2 treatment arms (Chronocort minus Cortef) was wholly above minus 15 percentage points.
    [2] - One-sided non-inferiority. The Ge et al (2011) method was used to calculate the estimate, standard error, confidence interval and P-value for the treatment difference from the results of a logistic regression analysis.

    Secondary: Total daily dose of hydrocortisone at Week 28

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    End point title
    		 Total daily dose of hydrocortisone at Week 28
    End point description
    Least squares (LS) mean was assessed using mixed model repeated measures (MMRM). Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    25
    28
    Units: mg
        least squares mean (confidence interval 95%)
    20.2 (17.8 to 22.6)
    26.0 (23.7 to 28.3)
    Statistical analysis title
    		 Analysis of Total Daily Dose of Hydrocortisone
    Comparison groups
    Chronocort v Cortef
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0005 [4]
    Method
    		 MMRM
    Parameter type
    		 Treatment Difference
    Point estimate
    -5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2
         upper limit
    		 -2.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.66
    Notes
    [3] - Superiority of Chronocort to Cortef was declared if the two-sided 95% CI for difference in means between the 2 treatment arms (Chronocort minus Cortef) was wholly below zero, provided that non-inferiority of Chronocort to Cortef in terms of biochemical response had been declared under the primary efficacy objective, and superiority of Chronocort to Cortef in terms of dose response has been declared.
    [4] - One sided-superiority.

    Secondary: Percentage of participants who were dose responders at Week 28

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    End point title
    		 Percentage of participants who were dose responders at Week 28
    End point description
    Dose response was defined as a participant who a) was receiving a total daily dose of hydrocortisone of not more than 25 mg and b) was in biochemical control at the 08:00 assessment. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    25
    28
    Units: percentage of participants
        number (not applicable)
    36.0
    10.7
    Statistical analysis title
    		 Analysis of Dose Responders
    Comparison groups
    Chronocort v Cortef
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.012 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment Difference
    Point estimate
    25.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.3
         upper limit
    		 47.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.24
    Notes
    [5] - Superiority of Chronocort to Cortef with respect to the dose response after 28 weeks of randomized treatment was declared if the two-sided 95% CI for the difference in response rates between the 2 treatment arms (Chronocort minus Cortef) was wholly above zero, provided that non-inferiority of Chronocort to Cortef with respect to the biochemical response had been declared under the primary efficacy objective.
    [6] - One-sided superiority. The Ge et al (2011) method was used to calculate the estimate, standard error, confidence interval and P-value for the treatment difference from the results of a logistic regression analysis.

    Secondary: Percentage of participants in biochemical control

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    End point title
    		 Percentage of participants in biochemical control
    End point description
    Biochemical control was defined as both a 17-OHP concentration (assessed at 08:00) equal to or below the upper limit for optimal control (1200 ng/dL [36.4 nmol/L]) and an A4 concentration equal to or below the upper limit of the reference range (150 ng/dL [5.2 nmol/L] for men and 200 ng/dL [7.0 nmol/L] for women). Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    25
    25 [7]
    Units: percentage of participants
    number (not applicable)
        Baseline
    52.0
    28.6
        Week 28
    40.0
    16.0
    Notes
    [7] - Baseline: n=27 Week 28: n=25
    No statistical analyses for this end point

    Secondary: Change from baseline in mean of 08:00 and 13:00 A4 levels at Week 28

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    End point title
    		 Change from baseline in mean of 08:00 and 13:00 A4 levels at Week 28
    End point description
    LS mean was assessed using ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    25
    25
    Units: ng/dL
        least squares mean (confidence interval 95%)
    -4.85 (-115.57 to 105.86)
    146.13 (35.42 to 256.85)
    No statistical analyses for this end point

    Secondary: Change from baseline in mean of 08:00 and 13:00 17-OHP levels at Week 28

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    End point title
    		 Change from baseline in mean of 08:00 and 13:00 17-OHP levels at Week 28
    End point description
    LS mean was assessed using analysis of covariance (ANCOVA). Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    25
    25
    Units: ng/dL
        least squares mean (confidence interval 95%)
    -1223.91 (-2897.42 to 449.6)
    1612.17 (-61.34 to 3285.68)
    No statistical analyses for this end point

    Secondary: Percentage of participants with menstrual regularity (females of childbearing potential only)

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    End point title
    		 Percentage of participants with menstrual regularity (females of childbearing potential only)
    End point description
    Data are presented for the number of participants with more than monthly menstrual cycles, monthly menstrual cycles, and number of participants with oligomenorrhoea and amenorrhoea. Oligomenorrhoea was defined as fewer than 9 menstrual cycles per year or cycle length >35 days and amenorrhoea as absent menses for ≥ 3 months. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Only female participants of childbearing potential with evaluable data for the endpoint were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    14
    12
    Units: percentage of participants
    number (not applicable)
        More than Monthly
    0
    0
        Monthly
    64.3
    16.7
        Oligomenorrhoea
    14.3
    33.3
        Amenorrhoea
    21.4
    50.0
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in size of testicular adrenal rest tumors (males Only) at Week 28

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    End point title
    		 Percent Change From Baseline in size of testicular adrenal rest tumors (males Only) at Week 28
    End point description
    Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Only male participants with evaluable data for the endpoint were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    4
    5
    Units: percent change
        arithmetic mean (standard deviation)
    -7.67 ( 9.220 )
    -0.90 ( 1.810 )
    No statistical analyses for this end point

    Secondary: Change from baseline in luteinizing hormone levels (males only) at Week 28

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    End point title
    		 Change from baseline in luteinizing hormone levels (males only) at Week 28
    End point description
    LS mean was assessed using ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Only male participants with evaluable data for the endpoint were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    9
    10
    Units: mIU/mL
        least squares mean (confidence interval 95%)
    0.15 (-0.71 to 1.02)
    -1.19 (-2.01 to -0.37)
    No statistical analyses for this end point

    Secondary: Change from baseline in hirsutism at Week 28 using the Ferriman-Gallwey score (females only) at Week 28

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    End point title
    		 Change from baseline in hirsutism at Week 28 using the Ferriman-Gallwey score (females only) at Week 28
    End point description
    Ferriman-Gallwey score is a method used to assess and quantify hirsutism in women. A total score < 8 is considered normal whereas a score of 8 to 15 indicates mild hirsutism. A score >15 indicates moderate or severe hirsutism. The Ferriman-Gallwey score ranged from 0 to 36. Higher score indicated more hirsutism. Change from baseline is reported (negative change from baseline indicated improvement). LS mean was assessed using ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Only female participants with evaluable data for the endpoint were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    16
    13
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -1.0 (-2.5 to 0.6)
    -1.2 (-3.0 to 0.5)
    No statistical analyses for this end point

    Secondary: Change from baseline in acne using the Global Evaluation Acne (GEA) scale (females only) at Week 28

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    End point title
    		 Change from baseline in acne using the Global Evaluation Acne (GEA) scale (females only) at Week 28
    End point description
    Acne severity was assessed according to GEA scale, which ranged from 0 (Clear. No lesions) to 5 (Very severe). Higher score indicated higher severity of acne. Change from baseline is reported (negative change from baseline indicated improvement). LS mean was assessed using ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Only female participants with evaluable data for the endpoint were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    16
    13
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -0.3 (-0.5 to -0.1)
    -0.2 (-0.4 to 0.0)
    No statistical analyses for this end point

    Secondary: Change from baseline in waist circumference at Week 28

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    End point title
    		 Change from baseline in waist circumference at Week 28
    End point description
    LS mean was assessed using ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    24
    24
    Units: centimeters
        least squares mean (confidence interval 95%)
    0.867 (-1.387 to 3.121)
    -1.242 (-3.496 to 1.012)
    No statistical analyses for this end point

    Secondary: Change from baseline in glycated hemoglobin (HbA1c) percent levels at Week 28

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    End point title
    		 Change from baseline in glycated hemoglobin (HbA1c) percent levels at Week 28
    End point description
    LS mean was assessed by ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    22
    24
    Units: percent HbA1c
        least squares mean (confidence interval 95%)
    -0.01 (-0.09 to 0.06)
    -0.06 (-0.13 to 0.01)
    No statistical analyses for this end point

    Secondary: Change from baseline in body weight at Week 28

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    End point title
    		 Change from baseline in body weight at Week 28
    End point description
    LS mean was assessed by ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and who received at least 1 dose of study drug. Participants with evaluable data for the endpoint were analyzed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    25
    25
    Units: kilograms
        least squares mean (confidence interval 95%)
    1.29 (0.00 to 2.58)
    -1.67 (-2.96 to -0.38)
    No statistical analyses for this end point

    Secondary: Change from baseline quality of life using the self-completed Medical Outcome Study 36-Item Short Form Health Survey (SF-36) total score for the physical and mental components and the sub-domain of vitality at Week 28

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    End point title
    		 Change from baseline quality of life using the self-completed Medical Outcome Study 36-Item Short Form Health Survey (SF-36) total score for the physical and mental components and the sub-domain of vitality at Week 28
    End point description
    SF-36 evaluates aspects of functional health and well-being. Physical component has 4 sub-scales: physical function, role limitations due to physical problems, pain, and general health perception; and mental component has 4 sub-scales: vitality, social function, role limitations due to emotional problems, and mental health. Total scores for the physical and mental component are presented as well as the sub-scale score for vitality. Scores were summarized and transformed into a range from 0 to 100; 0=worst, and 100=best outcome. Higher scores indicated better outcome. Change from baseline is reported (positive change from baseline indicated improvement. LS mean was assessed by ANCOVA. Assessment of efficacy at Week 28 was a composite of each participant's on-treatment visit closest in time to 28 weeks post randomisation. FAS: All participants with CAH who were randomized into the study and received at least 1 dose of study drug. Participants with evaluable data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 28
    End point values
    		 Chronocort Cortef
    Number of subjects analysed
    21
    15
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Physical Component
    -3.313 (-5.801 to -0.824)
    -1.031 (-3.976 to 1.913)
        Mental Component
    0.772 (-3.209 to 4.752)
    0.685 (-4.034 to 5.403)
        Vitality Sub-domain
    -0.847 (-4.354 to 2.660)
    -0.002 (-4.157 to 4.153)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days after last study dose (maximum treatment duration of approximately 53 weeks; median exposure = 255.0 days for Chronocort and 230.5 days for Cortef)
    Adverse event reporting additional description
    The Cortef and Chronocort reporting groups were assessed using the safety analysis set that included all participants who were randomized and received at least 1 dose of study drug in the treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Cortef
    Reporting group description
    		 Participants received Cortef at a starting dose of 30 mg, with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding.

    Reporting group title
    Chronocort
    Reporting group description
    		 Participants received Chronocort at a starting dose of 30 mg, with dose adjustments down to 25, 20, or 15 mg based on adrenal insufficiency symptoms and androgen levels. Placebo was used for dose adjustment to maintain blinding.

    Serious adverse events
    		 Cortef Chronocort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 25 (8.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cortef Chronocort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 28 (85.71%)
    22 / 25 (88.00%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 25 (4.00%)
         occurrences all number
    4
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 25 (8.00%)
         occurrences all number
    1
    2
    Weight increased
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 28 (10.71%)
    4 / 25 (16.00%)
         occurrences all number
    4
    4
    Dizziness
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 25 (8.00%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 28 (21.43%)
    0 / 25 (0.00%)
         occurrences all number
    6
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 25 (4.00%)
         occurrences all number
    2
    1
    Fatigue
         subjects affected / exposed
    5 / 28 (17.86%)
    4 / 25 (16.00%)
         occurrences all number
    5
    6
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 25 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 25 (8.00%)
         occurrences all number
    2
    2
    Psychiatric disorders
    Stress
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0
    Arthralgia
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 25 (12.00%)
         occurrences all number
    2
    3
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 25 (8.00%)
         occurrences all number
    1
    2
    Ear infection
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 25 (4.00%)
         occurrences all number
    2
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 25 (8.00%)
         occurrences all number
    2
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 25 (8.00%)
         occurrences all number
    3
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2021
    • Amended blinding procedure to avoid inadvertent unblinding • Allowed access to commercial Chronocort, depending on the territory
    27 Jan 2022
    • Added additional exclusion criteria • Changed maximum blood volume to be drawn during the study • Clarified concomitant therapy • Added section for interactions with other medicinal product • Expended on Dose Modification reasons • Added section for COVID-19 Procedures • New section added on remote monitoring visits
    04 Mar 2022
    • Revised schedule of assessment • Clarified exclusion criteria • Clarified rescue medication • Clarified participant discontinuation • Clarified dosing schedule • Amended serious adverse event reporting procedure • Clarified fasting requirements • Revised Clinical Laboratory Tests
    23 Mar 2022
    • Correction made to schedule of assessments • Clarified study assessments and procedures • Clarified adverse event definition
    09 Feb 2023
    • Duration of the fixed-dose period has been reduced from 36 weeks to 12 weeks and the number of patients reduced from approximately 150 to approximately 50 (or an enrolment cut-off date of 30 April 2023, whichever is reached first)
    30 Oct 2023
    • Revised non-inferiority margin • Clarified when last dose of study medication will be taken • Clarified EOS visit sample analysis • Clarified procedure for recording of physical examination findings

    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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