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    Clinical Trial Results:
    A randomized double blind cross-over study of the effects of low dose and high dose hydrocortisone replacement therapy on cognition, quality of life, metabolic profile and somatosensation in patients with secondary adrenal insufficiency

    Summary
    EudraCT number
    		 2011-000864-82
    Trial protocol
    		 NL  
    Global end of trial date
    12 Jun 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Feb 2016
    First version publication date
    26 Jun 2014
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    hydrocortisone
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01546922
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ABR : 35668
    Sponsors
    Sponsor organisation name
    University Medical Center Groningen
    Sponsor organisation address
    Department of Endocrinology, AA31, Postbus 30.001, GRONINGEN, Netherlands, 9700 RB
    Public contact
    Department of Endocrinology, University Medical Center Groningen, +31 503613962, n.alma@umcg.nl
    Scientific contact
    Department of Endocrinology, University Medical Center Groningen, +31 503613962, n.alma@umcg.nl
    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
    30 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jun 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to investigate whether a physiologically low HC dose is better for cognition as compared to a high HC dose.
    Protection of trial subjects
    Additional hydrocortisone escape medication to provide an imitation of a physiological stress response is allowed. The pharmacy of the UMCG was able to break the randomisation code in case of experienced serious discomfort in the patients' physical or mental functioning caused by the new hydrocortisone dose. Adverse events were assessed systematically during the scheduled visits to the hospital and halfway during a treatment period.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jan 2012
    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
    Netherlands: 63
    Worldwide total number of subjects
    63
    EEA total number of subjects
    63
    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)
    55
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 63 patients were included. Patients on cortisone acetate were converted to hydrocortisone in a bioequivalent dose during the run-in phase. Three patients withdrew during the run-in phase, therefore a total of 60 patients started the treatment periods.

    Period 1
    Period 1 title
    First period of ten weeks
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 First a low dose HC followed by a high dose HC
    Arm description
    		 In this arm patients first received a low dose of hydrocortisone for ten weeks followed by a high dose of hydrocortisone for ten weeks.
    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 received 0.2-0.3 mg hydrocortisone per kg body weight

    Arm title
    		 First a high dose HC followed by a low dose HC
    Arm description
    		 In this arm patients first received a high dose of hydrocortisone for ten weeks followed by a low dose of hydrocortisone for ten weeks
    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 received 0.4-0.6 mg hydrocortisone per kg body weight

    Number of subjects in period 1
    		First a low dose HC followed by a high dose HC First a high dose HC followed by a low dose HC
    Started
    30
    30
    Completed
    25
    28
    Not completed
    5
    2
         Consent withdrawn by subject
    1
    1
         Broken arm, investigators judgement
    1
    -
         Protocol deviation
    3
    1
    Period 2
    Period 2 title
    Second period of ten weeks
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 First a low dose HC followed by a high dose HC
    Arm description
    		 In this arm patients first received a low dose of hydrocortisone for ten weeks followed by a high dose of hydrocortisone for ten weeks.
    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 received 0.4-0.6 mg hydrocortisone per kg body weight

    Arm title
    		 First a high dose HC followed by a low dose HC
    Arm description
    		 In this arm patients first received a high dose of hydrocortisone for ten weeks followed by a low dose of hydrocortisone for ten weeks
    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 received 0.2-0.3 mg hydrocortisone per kg body weight

    Number of subjects in period 2
    		First a low dose HC followed by a high dose HC First a high dose HC followed by a low dose HC
    Started
    25
    28
    Completed
    22
    25
    Not completed
    3
    3
         Consent withdrawn by subject
    -
    2
         Protocol deviation
    3
    1
    Period 3
    Period 3 title
    Completed both study periods
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Subjects receiving a low dose of 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
    Patients received 0.2-0.3 mg hydrocortisone per kg body weight

    Arm title
    		 Subject receiving a high dose of 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
    Patients received 0.4-0.6 mg hydrocortisone per kg body weight

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristics are based on the 47 patients that completed both study periods.
    Number of subjects in period 3
    		Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Started
    47
    47
    Completed
    47
    47

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Completed both study periods
    Reporting group description
    		 -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on the 47 patients that completed both study periods.
    Reporting group values
    		 Completed both study periods Total
    Number of subjects
    		 47 47
    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
        median (inter-quartile range (Q1-Q3))
    		 55 (43 to 61) -
    Gender categorical
    Units: Subjects
        Female
    		 18 18
        Male
    		 29 29
    Childhood onset / Adult onset
    Units: Subjects
        Childhood onset
    		 6 6
        Adult onset
    		 41 41
    Type of surgery
    Units: Subjects
        Transsphenoïdal surgery
    		 23 23
        Craniotomy
    		 9 9
        No surgery
    		 15 15
    Patients with a second surgery
    Units: Subjects
        Second surgery
    		 5 5
        No second surgery
    		 42 42
    Type of radiotherapy
    Units: Subjects
        Pituitary radiotherapy
    		 16 16
        Cranial irradiation
    		 2 2
        Radiotherapy for extracranial tumors
    		 1 1
        No radiotherapy
    		 28 28
    Number of daily dosings prior to randomization
    Units: Subjects
        1 dose per day
    		 3 3
        2 doses per day
    		 33 33
        3 doses per day
    		 11 11
    Number of hormonal replacements
    Units: Subjects
        1 hormonal replacement
    		 3 3
        2 hormonal replacements
    		 9 9
        3 hormonal replacements
    		 21 21
        4 hormonal replacements
    		 11 11
        5 hormonal replacements
    		 3 3
    Thyroid hormone
    Units: Subjects
        Substituted
    		 43 43
        Unsubstituted
    		 4 4
    Growth hormone
    Units: Subjects
        Substituted
    		 21 21
        Unsubstituted - growth hormone deficiency
    		 10 10
        Unsubstituted - no growth hormone deficiency
    		 16 16
    Sex hormone
    Units: Subjects
        Men: testosterone
    		 23 23
        Premenopausal women: estrogen
    		 4 4
        Unsubstituted
    		 20 20
    Desmopressin substitution
    Units: Subjects
        Substituted
    		 9 9
        Unsubstituted
    		 38 38
    Age at diagnosis
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 31 (20 to 46) -
    Body weight
    Units: kg
        median (inter-quartile range (Q1-Q3))
    		 82.5 (72.2 to 93) -
    Age at surgery
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 39 (28 to 50) -
    Time since surgery
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 11 (6 to 20) -
    Age at radiotherapy
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 43 (25 to 52) -
    Time since radiotherapy
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 12 (9 to 22) -
    Total daily dose hydrocortisone treatment prior to randomization
    Units: mg/day
        median (inter-quartile range (Q1-Q3))
    		 25 (20 to 30) -
    Dose per kg body weight prior to randomization
    Units: mg/kg body weight
        median (inter-quartile range (Q1-Q3))
    		 0.32 (0.25 to 0.35) -
    Duration of hydrocortisone treatment prior to randomization
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 12 (5 to 22) -

    End points

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    End points reporting groups
    Reporting group title
    First a low dose HC followed by a high dose HC
    Reporting group description
    		 In this arm patients first received a low dose of hydrocortisone for ten weeks followed by a high dose of hydrocortisone for ten weeks.

    Reporting group title
    First a high dose HC followed by a low dose HC
    Reporting group description
    		 In this arm patients first received a high dose of hydrocortisone for ten weeks followed by a low dose of hydrocortisone for ten weeks
    Reporting group title
    First a low dose HC followed by a high dose HC
    Reporting group description
    		 In this arm patients first received a low dose of hydrocortisone for ten weeks followed by a high dose of hydrocortisone for ten weeks.

    Reporting group title
    First a high dose HC followed by a low dose HC
    Reporting group description
    		 In this arm patients first received a high dose of hydrocortisone for ten weeks followed by a low dose of hydrocortisone for ten weeks
    Reporting group title
    Subjects receiving a low dose of hydrocortisone
    Reporting group description
    		 -

    Reporting group title
    Subject receiving a high dose of hydrocortisone
    Reporting group description
    		 -

    Primary: RBMT - immediate memory

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    End point title
    		 RBMT - immediate memory
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.41 ( 0.95 )
    -0.42 ( 1.33 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.861 [1]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: RBMT - delayed memory

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    End point title
    		 RBMT - delayed memory
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.07 ( 0.98 )
    0.1 ( 1.33 )
    Statistical analysis title
    		 Low dose versus high dose
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.668 [2]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: RBMT - delayed corrected for immediate memory

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    End point title
    		 RBMT - delayed corrected for immediate memory
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.85 ( 1.09 )
    0.89 ( 1.34 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.713 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: 15 Words Test - Short-term memory

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    End point title
    		 15 Words Test - Short-term memory
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.36 ( 1.01 )
    -0.03 ( 1.03 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.028 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: 15 Words Test - Total immediate memory

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    End point title
    		 15 Words Test - Total immediate memory
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.43 ( 1.02 )
    0.25 ( 0.92 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.227 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: 15 Words Test - Learning score

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    End point title
    		 15 Words Test - Learning score
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.08 ( 1.05 )
    0.38 ( 1.19 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.13 [6]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: 15 Words Test - Delayed memory

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    End point title
    		 15 Words Test - Delayed memory
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.02 ( 1.04 )
    0.23 ( 0.97 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.106 [7]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: 15 Words Test - Delayed corrected for total memory

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    End point title
    		 15 Words Test - Delayed corrected for total memory
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.3 ( 0.99 )
    -0.16 ( 0.99 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.35 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: 15 Words Test - Recognition

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    End point title
    		 15 Words Test - Recognition
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.11 ( 0.88 )
    0.08 ( 0.71 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.093 [9]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [9] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Digit Span forward

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    End point title
    		 Digit Span forward
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.49 ( 0.97 )
    0.56 ( 0.97 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.614 [10]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [10] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Rey Complex Figure - Immediate memory

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    End point title
    		 Rey Complex Figure - Immediate memory
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    1.14 ( 1.26 )
    1.4 ( 1.29 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.111 [11]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Rey Complex Figure - delayed memory

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    End point title
    		 Rey Complex Figure - delayed memory
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    1.11 ( 1.22 )
    1.28 ( 1.29 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.451 [12]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [12] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Divided attention - reaction time auditory responses

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    End point title
    		 Divided attention - reaction time auditory responses
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.87 ( 0.81 )
    -0.89 ( 0.82 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.905 [13]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [13] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Divided attention - reaction time visual response

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    End point title
    		 Divided attention - reaction time visual response
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.06 ( 1 )
    0.03 ( 0.94 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.502 [14]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [14] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Divided attention - Number of omission errors

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    End point title
    		 Divided attention - Number of omission errors
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.02 ( 0.86 )
    -0.14 ( 0.93 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.531 [15]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Divided attention - Number of commission errors

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    End point title
    		 Divided attention - Number of commission errors
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.3 ( 1.01 )
    0.34 ( 0.76 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.681 [16]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [16] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Visual scanning - reaction time for target stimuli

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    End point title
    		 Visual scanning - reaction time for target stimuli
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.38 ( 1.04 )
    -0.36 ( 1.03 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.713 [17]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [17] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Visual scanning - Number of omission errors

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    End point title
    		 Visual scanning - Number of omission errors
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.03 ( 1.06 )
    0.08 ( 1.08 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.229 [18]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [18] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Visual scanning - Number of commission errors

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    End point title
    		 Visual scanning - Number of commission errors
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.72 ( 0.26 )
    -0.7 ( 0.28 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.329 [19]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [19] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Alertness - Reaction time tonic alertness

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    End point title
    		 Alertness - Reaction time tonic alertness
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.9 ( 0.73 )
    -0.99 ( 0.73 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.192 [20]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [20] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Alertness - Reaction time phasic alertness

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    End point title
    		 Alertness - Reaction time phasic alertness
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -1.03 ( 0.67 )
    -1.1 ( 0.66 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.164 [21]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [21] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Semantic fluency

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    End point title
    		 Semantic fluency
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.02 ( 1.24 )
    0.09 ( 1.18 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subject receiving a high dose of hydrocortisone v Subjects receiving a low dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.536 [22]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [22] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Phonemic fluency

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    End point title
    		 Phonemic fluency
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.32 ( 1.48 )
    0.21 ( 1.31 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.572 [23]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [23] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Digit span backward

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    End point title
    		 Digit span backward
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.05 ( 0.86 )
    -0.01 ( 1.02 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.632 [24]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [24] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Trail Making Test - Condition A

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    End point title
    		 Trail Making Test - Condition A
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.32 ( 1.14 )
    -0.26 ( 1.06 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.512 [25]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [25] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Trail Making Test - Condition B

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    End point title
    		 Trail Making Test - Condition B
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.16 ( 1.46 )
    0.18 ( 1.31 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.861 [26]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [26] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Trail Making Test - Condition B/A

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    End point title
    		 Trail Making Test - Condition B/A
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    0.37 ( 1.42 )
    0.36 ( 1.48 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.958 [27]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [27] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Primary: Social cognition

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    End point title
    		 Social cognition
    End point description
    End point type
    Primary
    End point timeframe
    Cognitive performance was measured after each treatment period.
    End point values
    		 Subjects receiving a low dose of hydrocortisone Subject receiving a high dose of hydrocortisone
    Number of subjects analysed
    47
    47
    Units: Zscore
        arithmetic mean (standard deviation)
    -0.67 ( 1.2 )
    -0.71 ( 1.15 )
    Statistical analysis title
    		 Low dose of HC versus high dose of HC
    Statistical analysis description
    Comparison of cognitive performance on the low dose of hydrocortisone and the high dose of hydrocortisone.
    Comparison groups
    Subjects receiving a low dose of hydrocortisone v Subject receiving a high dose of hydrocortisone
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.819 [28]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [28] - We've applied a Bonferroni correction, setting the significance level at <0.001.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed after 5 and 10 weeks during each treatment period.
    Adverse event reporting additional description
    Patients were able to report adverse events in between assessment points when necessary.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Not specified
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Low dose of hydrocortisone
    Reporting group description
    		 Adverse events while patients received a low dose of hydrocortisone

    Reporting group title
    High dose of hydrocortisone
    Reporting group description
    		 Adverse events while patients received a high dose of hydrocortisone

    Serious adverse events
    		 Low dose of hydrocortisone High dose of hydrocortisone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 55 (1.82%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Minor stroke left cerebral hemisphere
    Additional description: A minor stroke in the left cerebral hemisphere
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza A infection
    Additional description: Influenza A infection resulting in hospitalization
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 55 (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
    		 Low dose of hydrocortisone High dose of hydrocortisone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 58 (25.86%)
    9 / 55 (16.36%)
    Injury, poisoning and procedural complications
    Broken arm
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Fall from a horse
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Motorcycle accident
    Additional description: Accident with a motorcycle, knee slightly injured.
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Cardiac disorders
    Cardiac catherisation
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Tiredness
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 55 (1.82%)
         occurrences all number
    3
    1
    Dizziness
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 55 (1.82%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Stiffness in joints
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 55 (1.82%)
         occurrences all number
    1
    1
    Immune system disorders
    Allergic reaction to Ibuprofen
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Eye disorders
    Diplopia with surgical correction
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Gasteroenteritis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 55 (0.00%)
         occurrences all number
    2
    0
    Herpes zoster
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 55 (1.82%)
         occurrences all number
    1
    1
    Red spots in face
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Acne on back and forehead
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Depression
    Additional description: Progressive depression
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Cystitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Joint pain
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 55 (3.64%)
         occurrences all number
    2
    2
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 55 (1.82%)
         occurrences all number
    2
    1

    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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