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    Clinical Trial Results:
    A single centre, open label, randomised, crossover study in dexamethasone-suppressed healthy adult male volunteers to compare the pharmacokinetics of Infacort® versus immediate-release hydrocortisone tablets at a single dose of 10mg and to evaluate the dose proportionality of Infacort® at doses of 0.5mg, 2mg, 5mg and 10mg.

    Summary
    EudraCT number
    		 2013-000260-28
    Trial protocol
    		 GB  
    Global end of trial date
    09 Sep 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jun 2016
    First version publication date
    31 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Infacort 001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Diurnal Limited
    Sponsor organisation address
    Cardiff Medicentre, Cardiff, United Kingdom, CF14 4UJ
    Public contact
    info@diurnal.co.uk, Diurnal Limited, info@diurnal.co.uk
    Scientific contact
    info@diurnal.co.uk, Diurnal Limited, info@diurnal.co.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001283-PIP01-12
    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
    04 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objectives •To compare the pharmacokinetics of Infacort® versus immediate-release hydrocortisone in a single dose of 10mg. •To determine the dose proportionality for Infacort® at doses of 0.5mg, 2mg, 5mg and 10mg.
    Protection of trial subjects
    The study protocol (Version 1, 17 April 2013), volunteer consent form (Version 2, 8 May 2013) and subject information sheet (Version 2, 8 May 2013) were approved by the South East Wales Research Ethics Committees (REC) on 13 May 2013. Prior to undergoing any study-specific procedure, each potential study subject provided signed acknowledgement of their freely given informed consent. Either the Chief Investigator or a designated person, qualified to meet any applicable local regulations, who was equally knowledgeable about the study explained the aims, methods, anticipated benefits and potential hazards of the study and any discomfort it may have entailed. A corresponding written explanation (subject information sheet) was also provided and the subject allowed sufficient time to consider the study information. Prior to signing the consent form, the subject was given an opportunity to discuss any issues concerning the study with a physician who had suitable knowledge of the study and had all questions answered openly and honestly.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    16
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 16
    Number of subjects completed
    		 16

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Infacort 0.5 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Infacort 0.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Each subject received 0.5 mg Infacort granules from 1 x 0.5 mg capsule of IMP on the morning of Day 2 at ~ 07.00 hrs (fasted). The Infacort® capsules were opened, the entire contents (multi-particulate granules) emptied onto a dosing spoon, administered to the back of the subject’s tongue and swallowed with 200 mL water (100 mL to swallow the treatment and 100 mL rinse). Each subject also received 1 mg dexamethasone (to suppress endogenous cortisol production) at approximately 22.00 hrs on Day 1, and at approximately 06.00 hrs and 12.00 hrs on Day 2.

    Arm title
    		 Infacort 2 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Infacort 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Each subject received 2 mg Infacort granules from 1 x 2 mg capsule of IMP on the morning of Day 2 at ~ 07.00 hrs (fasted). The Infacort® capsules were opened, the entire contents (multi-particulate granules) emptied onto a dosing spoon, administered to the back of the subject’s tongue and swallowed with 200 mL water (100 mL to swallow the treatment and 100 mL rinse). Each subject also received 1 mg dexamethasone (to suppress endogenous cortisol production) at approximately 22.00 hrs on Day 1, and at approximately 06.00 hrs and 12.00 hrs on Day 2.

    Arm title
    		 Infacort 5 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Infacort 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Each subject received 5 mg of Infacort granules from 1 x 5 mg capsule on the morning of Day 2 at ~ 07.00 hrs (fasted). The Infacort® capsules were opened, the entire contents (multi-particulate granules) emptied onto a dosing spoon, administered to the back of the subject’s tongue and swallowed with 200 mL water (100 mL to swallow the treatment and 100 mL rinse). Each subject also received 1 mg dexamethasone (to suppress endogenous cortisol production) at approximately 22.00 hrs on Day 1, and at approximately 06.00 hrs and 12.00 hrs on Day 2.

    Arm title
    		 Infacort 10 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Infacort 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Each subject received 10 mg of Infacort granules from 2 x 5 mg capsules on the morning of Day 2 at ~ 07.00 hrs (fasted). The Infacort® capsules were opened, the entire contents (multi-particulate granules) emptied onto a dosing spoon, administered to the back of the subject’s tongue and swallowed with 200 mL water (100 mL to swallow the treatment and 100 mL rinse). Each subject also received 1 mg dexamethasone (to suppress endogenous cortisol production) at approximately 22.00 hrs on Day 1, and at approximately 06.00 hrs and 12.00 hrs on Day 2.

    Arm title
    		 Hydrocortisone
    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
    Each subject received 1 x 10 mg hydrocortisone tablet on the morning of Day 2 at ~07.00 hrs (fasted). The hydrocortisone tablets were swallowed whole with 200 mL water. Each subject also received 1 mg dexamethasone (to suppress endogenous cortisol production) at approximately 22.00 hrs on Day 1, and at approximately 06.00 hrs and 12.00 hrs on Day 2.

    Number of subjects in period 1
    		Infacort 0.5 mg Infacort 2 mg Infacort 5 mg Infacort 10 mg Hydrocortisone
    Started
    16
    16
    16
    16
    16
    Completed
    16
    16
    16
    16
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 16 16
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 16 16
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.7 ( 14.37 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 16 16

    End points

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    End points reporting groups
    Reporting group title
    Infacort 0.5 mg
    Reporting group description
    		 -

    Reporting group title
    Infacort 2 mg
    Reporting group description
    		 -

    Reporting group title
    Infacort 5 mg
    Reporting group description
    		 -

    Reporting group title
    Infacort 10 mg
    Reporting group description
    		 -

    Reporting group title
    Hydrocortisone
    Reporting group description
    		 -

    Primary: Bioequivalence: Cmax

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    End point title
    		 Bioequivalence: Cmax [1]
    End point description
    Unadjusted data excluding individual treatment profiles from subjects where the pre-dose cortisol demonstrated inadequate suppression.
    End point type
    Primary
    End point timeframe
    PK blood samples for measurement of serum cortisol levels were collected on Day 2 pre-dose (-1 hr and – 0.5 hr) and 0 hr (07.00 hrs), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11 and 12 hr post-dose
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are only presented for Infacort 10 mg and hydrocortisone tablets, in line with the primary end point.
    End point values
    		 Infacort 10 mg Hydrocortisone
    Number of subjects analysed
    14 [2]
    16
    Units: nmol/L
        geometric mean (standard deviation)
    604.467 ( 139.6942 )
    622.384 ( 99.3543 )
    Notes
    [2] - Subjects with inadequate cortisol suppression have been excluded.
    Statistical analysis title
    		 Infacort 10 mg vs Hydrocortisone 10 mg: Cmax
    Statistical analysis description
    To compare PK between treatments, the logarithms of these PK parameters were analysed using a mixed effects analysis of variance (ANOVA) including fixed effects for sequence, period and treatment and a random effect for subject nested within sequence. Based on the analyses, point estimates and 90% CI for the treatment ratios were calculated by re-transformation of the logarithmic results given by the ANOVA.
    Comparison groups
    Hydrocortisone v Infacort 10 mg
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Geometric least square mean
    Point estimate
    94.71
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 83.51
         upper limit
    		 107.4
    Notes
    [3] - Bioequivalence. N.B. The EudraCT form automatically sums the number of subjects in both treatment groups, which is incorrect as this is a cross-over design. The correct number of subjects in this analysis is 14. Statistical Analysis has been performed on baseline adjusted data.

    Primary: Bioequivalence: AUC0-t

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    End point title
    		 Bioequivalence: AUC0-t [4]
    End point description
    Unadjusted data excluding individual treatment profiles from subjects where the pre-dose cortisol demonstrated inadequate suppression.
    End point type
    Primary
    End point timeframe
    PK blood samples for measurement of serum cortisol levels were collected on Day 2 pre-dose (-1 hr and – 0.5 hr) and 0 hr (07.00 hrs), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11 and 12 hr post-dose
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are only presented for Infacort 10 mg and hydrocortisone tablets, in line with the primary end point.
    End point values
    		 Infacort 10 mg Hydrocortisone
    Number of subjects analysed
    14 [5]
    16
    Units: hr*nmol/L
        geometric mean (standard deviation)
    1785.306 ( 312.7802 )
    1803.278 ( 266.1113 )
    Notes
    [5] - Subjects with inadequate cortisol suppression have been excluded.
    Statistical analysis title
    		 Infacort 10 mg vs Hydrocortisone 10 mg: AUC0-t
    Statistical analysis description
    To compare PK between treatments, the logarothms of these PK parameters were analysed using a mixed effects analysis of variance (ANOVA) including fixed effects for sequence, period and treatment and a random effect for subject nested within sequence. Based on these analyses, point estimates and 90% CI for the treatment ratios were calculated by re-transformation of the logarithmic results given by the ANOVA.
    Comparison groups
    Infacort 10 mg v Hydrocortisone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Geometric least square mean
    Point estimate
    101.27
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 95.78
         upper limit
    		 107.09
    Notes
    [6] - Bioequivalence. N.B. The EudraCT form automatically sums the number of subjects in both treatment groups, which is incorrect as this is a cross-over design. The correct number of subjects in this analysis is 14. Statistical analysis has been performed on baseline adjusted data.

    Primary: Bioequivalence: AUC0-inf

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    End point title
    		 Bioequivalence: AUC0-inf [7]
    End point description
    Unadjusted data excluding individual treatment profiles from subjects where the pre-dose cortisol demonstrated inadequate suppression.
    End point type
    Primary
    End point timeframe
    PK blood samples for measurement of serum cortisol levels were collected on Day 2 pre-dose (-1 hr and – 0.5 hr) and 0 hr (07.00 hrs), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11 and 12 hr post-dose
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are only presented for Infacort 10 mg and hydrocortisone tablets, in line with the primary end point.
    End point values
    		 Infacort 10 mg Hydrocortisone
    Number of subjects analysed
    14 [8]
    16
    Units: hr*nmol/L
        geometric mean (standard deviation)
    1881.745 ( 311.6197 )
    1898.311 ( 295.1258 )
    Notes
    [8] - Subjects with inadequate cortisol suppression have been excluded.
    Statistical analysis title
    		 Infacort 10 mg vs Hydrocortisone 10 mg: AUC0-inf
    Statistical analysis description
    To compare PK between treatments, the logarithms of these PK parameters were analysed using a mixed effects analysis of variance (ANOVA) including fixed effects for sequence, period and treatment and a random effect for subject nested within sequence. Based on the analyses, point estimates and 90% CI for the treatment ratios were calculated by re-transformation of the logarithmic results given by the ANOVA.
    Comparison groups
    Infacort 10 mg v Hydrocortisone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 Geometric least square mean
    Point estimate
    101.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 95.45
         upper limit
    		 106.94
    Notes
    [9] - Bioequivalence. N.B. The EudraCT form automatically sums the number of subjects in both treatment groups, which is incorrect as this is a cross-over design. The correct number of subjects in this analysis is 14. Statistical analysis has been performed on baseline adjusted data.

    Primary: Bioequivalence: tmax

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    End point title
    		 Bioequivalence: tmax [10]
    End point description
    Unadjusted data excluding individual treatment profiles from subjects where the pre-dose cortisol demonstrated inadequate suppression.
    End point type
    Primary
    End point timeframe
    PK blood samples for measurement of serum cortisol levels were collected on Day 2 pre-dose (-1 hr and – 0.5 hr) and 0 hr (07.00 hrs), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11 and 12 hr post-dose
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are only presented for Infacort 10 mg and hydrocortisone tablets, in line with the primary end point.
    End point values
    		 Infacort 10 mg Hydrocortisone
    Number of subjects analysed
    14 [11]
    16
    Units: hr
        median (standard deviation)
    0.75 ( 0.4127 )
    1 ( 0.4171 )
    Notes
    [11] - Subjects with inadequate cortisol suppression have been excluded.
    Statistical analysis title
    		 Infacort 10 mg vs Hydrocortisone 10 mg: tmax
    Statistical analysis description
    An assessment of tmax was performed by using the Wilcoxon matched pairs test. In addition, a 95% non-parametric CI was constructed for the median difference in tmax based on the method of Campbell and Gardner.
    Comparison groups
    Infacort 10 mg v Hydrocortisone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.4772
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.25
    Notes
    [12] - Bioequivalence. N.B. The EudraCT form automatically sums the number of subjects in both treatment groups, which is incorrect as this is a cross-over design. The correct number of subjects in this analysis is 14. Statistical analysis has been performed on baseline adjusted data.

    Primary: Dose proportionality: Cmax

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    End point title
    		 Dose proportionality: Cmax [13]
    End point description
    Unadjusted data excluding individual treatment profiles from subjects where the pre-dose cortisol demonstrated inadequate suppression.
    End point type
    Primary
    End point timeframe
    PK blood samples for measurement of serum cortisol levels were collected on Day 2 pre-dose (-1 hr and – 0.5 hr) and 0 hr (07.00 hrs), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11 and 12 hr post-dose
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are only presented for Infacort 0.5 mg, 2 mg, 5 mg and 10 mg, in line with the primary end point.
    End point values
    		 Infacort 0.5 mg Infacort 2 mg Infacort 5 mg Infacort 10 mg
    Number of subjects analysed
    15 [14]
    16
    15 [15]
    14 [16]
    Units: nmol/L
        geometric mean (standard deviation)
    90.092 ( 20.1404 )
    242.798 ( 39.4013 )
    418.313 ( 59.8826 )
    604.467 ( 139.6942 )
    Notes
    [14] - Subjects with inadequate cortisol suppression have been excluded.
    [15] - Subjects with inadequate cortisol suppression have been excluded.
    [16] - Subjects with inadequate cortisol suppression have been excluded.
    Statistical analysis title
    		 Dose proportionality - Slope: Cmax
    Statistical analysis description
    Dose proportionality was assessed by performing a regression analysis of the log-transformed Cmax, AUC0-t and AUC0-inf values versus the log-transformed dose using the power model with a fixed effect for dose and a random effect for subject. For each parameter a point estimate and 95% CI has been calculated for the slope of the regression line.
    Comparison groups
    Infacort 0.5 mg v Infacort 2 mg v Infacort 5 mg v Infacort 10 mg
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    Method
    Parameter type
    		 Slope
    Point estimate
    0.702
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.658
         upper limit
    		 0.746
    Notes
    [17] - Dose-proportionality. N.B. The EudraCT form automatically sums the number of subjects in both treatment groups, which is incorrect as this is a cross-over design. The correct number of subjects in this analysis is 15. Statistical analysis has been performed on baseline adjusted data.

    Primary: Dose proportionality: AUC0-t

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    End point title
    		 Dose proportionality: AUC0-t [18]
    End point description
    Unadjusted data excluding individual treatment profiles from subjects where the pre-dose cortisol demonstrated inadequate suppression.
    End point type
    Primary
    End point timeframe
    PK blood samples for measurement of serum cortisol levels were collected on Day 2 pre-dose (-1 hr and – 0.5 hr) and 0 hr (07.00 hrs), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11 and 12 hr post-dose.
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are only presented for Infacort 0.5 mg, 2 mg, 5 mg and 10 mg, in line with the primary end point.
    End point values
    		 Infacort 0.5 mg Infacort 2 mg Infacort 5 mg Infacort 10 mg
    Number of subjects analysed
    15 [19]
    16
    15 [20]
    14 [21]
    Units: hr*nmol/L
        geometric mean (standard deviation)
    316.973 ( 57.2979 )
    648.407 ( 108.8652 )
    1111.031 ( 163.7324 )
    1785.306 ( 312.7802 )
    Notes
    [19] - Subjects with inadequate cortisol suppression have been excluded.
    [20] - Subjects with inadequate cortisol suppression have been excluded.
    [21] - Subjects with inadequate cortisol suppression have been excluded.
    Statistical analysis title
    		 Dose proportionality - Slope: AUC0-t
    Statistical analysis description
    Dose proportionality was assessed by performing a regression analysis of the log-transformed Cmax, AUC0-t and AUC0-inf values versus the log-transformed dose using the power model with a fixed effect for dose and a random effect for subject. For each parameter a point estimate and 95% CI has been calculated for the slope of the regression line.
    Comparison groups
    Infacort 0.5 mg v Infacort 2 mg v Infacort 5 mg v Infacort 10 mg
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    Method
    Parameter type
    		 Slope
    Point estimate
    0.858
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.833
         upper limit
    		 0.883
    Notes
    [22] - Dose-proportionality. N.B. The EudraCT form automatically sums the number of subjects in both treatment groups, which is incorrect as this is a cross-over design. The correct number of subjects in this analysis is 15. Statistical Analysis has been performed on baseline adjusted data.

    Primary: Dose proportionality: AUC0-inf

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    End point title
    		 Dose proportionality: AUC0-inf [23]
    End point description
    Unadjusted data excluding individual treatment profiles from subjects where the pre-dose cortisol demonstrated inadequate suppression.
    End point type
    Primary
    End point timeframe
    PK blood samples for measurement of serum cortisol levels were collected on Day 2 pre-dose (-1 hr and – 0.5 hr) and 0 hr (07.00 hrs), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11 and 12 hr post-dose.
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are only presented for Infacort 0.5 mg, 2 mg, 5 mg and 10 mg, in line with the primary end point.
    End point values
    		 Infacort 0.5 mg Infacort 2 mg Infacort 5 mg Infacort 10 mg
    Number of subjects analysed
    15 [24]
    16
    15 [25]
    14 [26]
    Units: hr*nmol/L
        geometric mean (standard deviation)
    505.706 ( 161.927 )
    790.269 ( 143.6361 )
    1213.237 ( 241.5286 )
    1881.745 ( 311.6197 )
    Notes
    [24] - Subjects with inadequate cortisol suppression have been excluded.
    [25] - Subjects with inadequate cortisol suppression have been excluded.
    [26] - Subjects with inadequate cortisol suppression have been excluded.
    Statistical analysis title
    		 Dose proportionality - Slope: AUC0-inf
    Statistical analysis description
    Dose proportionality was assessed by performing a regression analysis of the log-transformed Cmax, AUC0-t and AUC0-inf values versus the log-transformed dose using the power model with a fixed effect for dose and a random effect for subject. For each parameter a point estimate and 95% CI has been calculated for the slope of the regression line.
    Comparison groups
    Infacort 0.5 mg v Infacort 2 mg v Infacort 5 mg v Infacort 10 mg
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    Method
    Parameter type
    		 Slope
    Point estimate
    0.855
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.829
         upper limit
    		 0.881
    Notes
    [27] - Dose-proportionality. N.B. The EudraCT form automatically sums the number of subjects in both treatment groups, which is incorrect as this is a cross-over design. The correct number of subjects in this analysis is 15. Statistical analysis was performed using baseline adjusted data.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Only treatment-emergent AEs (TEAEs), i.e. existing conditions that worsened or events that occurred during the course of the study after administration of study drug, are included within the summary tables.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Infacort 0.5 mg
    Reporting group description
    		 -

    Reporting group title
    Infacort 2 mg
    Reporting group description
    		 -

    Reporting group title
    Infacort 5 mg
    Reporting group description
    		 -

    Reporting group title
    Infacort 10 mg
    Reporting group description
    		 -

    Reporting group title
    Hydrocortisone
    Reporting group description
    		 -

    Serious adverse events
    		 Infacort 0.5 mg Infacort 2 mg Infacort 5 mg Infacort 10 mg Hydrocortisone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Infacort 0.5 mg Infacort 2 mg Infacort 5 mg Infacort 10 mg Hydrocortisone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    4 / 16 (25.00%)
    1 / 16 (6.25%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Nausea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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