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    Clinical Trial Results:
    ADRENAL- ADjunctive coRticosteroid trEatment iN criticAlly ilL patients with septic shock.

    Summary
    EudraCT number
    		 2012-003158-10
    Trial protocol
    		 GB   DK   IE  
    Global end of trial date
    03 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Mar 2021
    First version publication date
    04 Mar 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GI-CCT372273
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01448109
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ANZCTR: ACTRN12611001042932
    Sponsors
    Sponsor organisation name
    The George Institute
    Sponsor organisation address
    Level 5/1 King St, Newtown, Sydney, Australia, 2042
    Public contact
    Dr. Anders Perner, Intensiv Terapiklinik 4131, 0045 354583333, anders.perner@regionh.dk
    Scientific contact
    Dr. Anders Perner, Intensiv Terapiklinik 4131, 0045 354583333, anders.perner@regionh.dk
    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
    31 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the impact of intravenous hydrocortisone versus placebo on all cause mortality at 90 days in critically ill patients with septic shock. The hypothesis is that hydrocortisone, compared to placebo, reduces 90-day all-cause mortality in patients admitted to an ICU with septic shock.
    Protection of trial subjects
    Double blinded trial and individual data were not shown to summary report.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 355
    Country: Number of subjects enrolled
    Denmark: 142
    Country: Number of subjects enrolled
    Australia: 2719
    Country: Number of subjects enrolled
    New Zealand: 420
    Country: Number of subjects enrolled
    Saudi Arabia: 164
    Worldwide total number of subjects
    3800
    EEA total number of subjects
    142
    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)
    1920
    From 65 to 84 years
    1751
    85 years and over
    129

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment from June2012 to April2017, location in hospital ICU

    Pre-assignment
    Screening details
    		 21818 patients were screened. In details, 16317 were ineligible (8054 did not meet inclusion criteria and 8263 met exclusion criteria); 1701 were eligible but excluded, (446 patients or SDM declined or unable to consent, 659 decline to randomize eligible patients, 95 patients were enrolled in another trial, 501 had other reasons/missing)

    Period 1
    Period 1 title
    Baseline Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    The above roles were blinded to study treatment allocation. The hydrocortisone sodium succinate sterile powder (equivalent to 100mg of hydrocortisone) has been sourced from the manufacturer of the registered product & supplied in glass vial. The powder is a white or nearly white odourless, hygroscopic amorphous solid which is soluble in water. The placebo is a matching vial holding 0.2 mL sterile water for injection. Hydrocortisone and placebo vials will be covered in blinding label + kit number

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Hydrocortisone
    Arm description
    		 IV hydrocortisone 200 mg/day for 7 days or until death or discharge from ICU
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Solu-CORTEF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    200mg/day for 7 days. Intravenous administration.

    Arm title
    		 Placebo
    Arm description
    		 placebo, for 7 days or until death or discharge from ICU
    Arm type
    		 Placebo

    Investigational medicinal product name
    PR1
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 Ampule in solution connected to an IV drip. Continuous infusion once per day for 7 days.

    Number of subjects in period 1
    		Hydrocortisone Placebo
    Started
    1898
    1902
    Oct 2014
    630 [1]
    629 [2]
    Jun 2016
    1249 [3]
    1251 [4]
    Completed
    1832
    1826
    Not completed
    66
    76
         Consent withdrawn by subject
    45
    42
         Lost to follow-up
    12
    -
         Partial withdrew consent
    9
    18
         Lost to follow-up
    -
    16
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestones referred to are each of the Data Safety Monitoring Board committee meetings. At each meeting more patients had been recruited and therefore the milestones had increased.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestones referred to are each of the Data Safety Monitoring Board committee meetings. At each meeting more patients had been recruited and therefore the milestones had increased.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestones referred to are each of the Data Safety Monitoring Board committee meetings. At each meeting more patients had been recruited and therefore the milestones had increased.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestones referred to are each of the Data Safety Monitoring Board committee meetings. At each meeting more patients had been recruited and therefore the milestones had increased.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Hydrocortisone
    Reporting group description
    		 IV hydrocortisone 200 mg/day for 7 days or until death or discharge from ICU

    Reporting group title
    Placebo
    Reporting group description
    		 placebo, for 7 days or until death or discharge from ICU

    Reporting group values
    		 Hydrocortisone Placebo Total
    Number of subjects
    		 1898 1902 3800
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 948 924 1872
        From 65-84 years
    		 847 869 1716
        85 years and over
    		 58 67 125
        Not recorded
    		 45 42 87
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.3 ( 14.9 ) 62.7 ( 15.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 734 720 1454
        Male
    		 1119 1140 2259
        Not recorded
    		 45 42 87
    Admission Type
    ICU admission diagnosis category
    Units: Subjects
        Medical
    		 1273 1266 2539
        Surgical
    		 576 591 1167
        Not recorded
    		 49 45 94
    Mechanical ventilation
    Baseline therapies
    Units: Subjects
        Yes
    		 1845 1855 3700
        No
    		 4 2 6
        Not recorded
    		 49 45 94
    Inotropes/vasopressors
    Baseline therapies
    Units: Subjects
        Yes
    		 1843 1854 3697
        No
    		 10 6 16
        Not recorded
    		 45 42 87
    Norepinephrine
    Baseline therapies
    Units: Subjects
        Yes
    		 1823 1821 3644
        No
    		 30 39 69
        Not recorded
    		 45 42 87
    Vasopressin
    Baseline therapies
    Units: Subjects
        Yes
    		 280 321 601
        No
    		 1573 1539 3112
        Not recorded
    		 45 42 87
    Epinephrine
    Baseline therapies
    Units: Subjects
        Yes
    		 134 113 247
        No
    		 1719 1747 3466
        Not recorded
    		 45 42 87
    Other baseline therapy
    Baseline therapies
    Units: Subjects
        Yes
    		 157 173 330
        No
    		 1696 1687 3383
        Not recorded
    		 45 42 87
    Antimicrobias use
    Baseline therapies
    Units: Subjects
        Yes
    		 1817 1821 3638
        No
    		 31 36 67
        Not recorded
    		 50 45 95
    Renal replacement therapy
    Baseline therapies
    Units: Subjects
        Yes
    		 228 242 470
        No
    		 1621 1615 3236
        Not recorded
    		 49 45 94
    Primary site of infection
    Baseline primary site of infection at admission diagnosis
    Units: Subjects
        Pulmonary
    		 623 677 1300
        Abdominal
    		 477 467 944
        Blood
    		 316 325 641
        Skin/soft tissue
    		 137 116 253
        Urinary
    		 146 133 279
        Others
    		 145 136 281
        Not recorded
    		 54 48 102
    Catecholamine dose
    Baseline catecholamine dose >15mcg/min
    Units: Subjects
        Yes
    		 981 1013 1994
        <15mcg/min
    		 853 819 1672
        Not recorded
    		 64 70 134
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 85.8 ( 26.6 ) 85.6 ( 26.2 ) -
    APACHE
    APACHE II Score
    Units: APACHE Units
        arithmetic mean (inter-quartile range (Q1-Q3))
    		 24 (19 to 29) 23 (18 to 29) -
    Heart Rate
    Units: beats/min
        arithmetic mean (standard deviation)
    		 96 ( 21.6 ) 95 ( 20.9 ) -
    MAP
    Units: mmhg
        arithmetic mean (standard deviation)
    		 72.5 ( 8.2 ) 72.2 ( 8.3 ) -
    CVP
    Units: mmHg
        arithmetic mean (standard deviation)
    		 12.0 ( 5.2 ) 12.1 ( 5.3 ) -
    Lowest MAP
    Lowest MAP in prior 24hrs
    Units: mmHg
        arithmetic mean (standard deviation)
    		 57.3 ( 8.5 ) 57.1 ( 9.1 ) -
    Lactate
    Highest lactate (mg/dL) in prior 24hrs
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 34.2 ( 29.1 ) 34.5 ( 28.2 ) -
    Bilirubin
    Highest bilirubin (mg/dL) in prior 24hrs
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 1.7 ( 2.4 ) 1.7 ( 2.4 ) -
    Creatinine
    Highest creatinine (mg/dL) in prior 24 hours
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 2.2 ( 2.0 ) 2.1 ( 1.7 ) -
    Lowest PaO2/FiO2
    Lowest PaO2/FiO2 in prior 24hrs
    Units: PaO2/FiO2 ratio
        arithmetic mean (standard deviation)
    		 164.6 ( 91.3 ) 166.4 ( 91.9 ) -
    Highest white cell count (10^9/L)
    Highest white cell count (10^9/L) in prior 24hrs
    Units: 10^9/L
        arithmetic mean (standard deviation)
    		 17.4 ( 11.4 ) 17.8 ( 14.7 ) -
    ICU admission to randomization (hrs)
    ICU admission to randomization (hrs)
    Units: hour
        arithmetic mean (standard deviation)
    		 26.1 ( 70.7 ) 28.9 ( 72.8 ) -
    Shock to randomization (hrs)
    Shock event onset to randomization (hrs)
    Units: hour
        arithmetic mean (standard deviation)
    		 20.9 ( 91.9 ) 21.2 ( 83.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Hydrocortisone
    Reporting group description
    		 IV hydrocortisone 200 mg/day for 7 days or until death or discharge from ICU

    Reporting group title
    Placebo
    Reporting group description
    		 placebo, for 7 days or until death or discharge from ICU

    Primary: 90-day mortality

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    End point title
    		 90-day mortality
    End point description
    End point type
    Primary
    End point timeframe
    Mortality at 90 days after randomisation
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1832 [1]
    1826 [2]
    Units: number
        Yes
    511
    526
    Notes
    [1] - missing subjects either withdrawn consent or lost to follow-up
    [2] - missing subjects either withdrawn consent or lost to follow-up
    Statistical analysis title
    		 Logistic regression model with random effect
    Statistical analysis description
    Statistical analysis description The primary outcome is presented as the odds ratio (OR) of death and the corresponding 95% confidence intervals (CI), analyzed using a logistic regression adjusted for stratification variables with medical vs. surgical diagnosis as a fixed effect and site as a random effect.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    3658
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.1
    Variability estimate
    Standard error of the mean

    Secondary: 28-day Mortality

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    End point title
    		 28-day Mortality
    End point description
    End point type
    Secondary
    End point timeframe
    Mortality at 28 days after randomisation
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1841
    1840
    Units: number
        Yes
    410
    448
    Statistical analysis title
    		 Logistic regression model with random effect
    Statistical analysis description
    The secondary outcome is presented as the odds ratio (OR) of death and the corresponding 95% confidence intervals (CI), analyzed using a logistic regression adjusted for stratification variables with medical vs. surgical diagnosis as a fixed effect and site as a random effect.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    3681
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.03
    Variability estimate
    Standard error of the mean

    Secondary: Reoccurence of shock

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    End point title
    		 Reoccurence of shock
    End point description
    End point type
    Secondary
    End point timeframe
    Reoccurence of shock after randomisation
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1853
    1860
    Units: number
        Yes
    365
    343
    Statistical analysis title
    		 Logistic regression model with random effect
    Statistical analysis description
    Statistical analysis description The secondary outcome is presented as the odds ratio (OR) and the corresponding 95% confidence intervals (CI), analyzed using a logistic regression adjusted for stratification variables with medical vs. surgical diagnosis as a fixed effect and site as a random effect.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    3713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.22
    Variability estimate
    Standard error of the mean

    Secondary: Reoccurence of mechanical ventilation

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    End point title
    		 Reoccurence of mechanical ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    Reoccurence of mechanical ventilation after randomisation
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1842
    1850
    Units: number
        Yes
    180
    154
    Statistical analysis title
    		 Logistic regression model with random effect
    Statistical analysis description
    The secondary outcome is presented as the odds ratio (OR) and the corresponding 95% confidence intervals (CI), analyzed using a logistic regression adjusted for stratification variables with medical vs. surgical diagnosis as a fixed effect and site as a random effect.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    3692
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.45
    Variability estimate
    Standard error of the mean

    Secondary: Use of RRT

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    End point title
    		 Use of RRT
    End point description
    End point type
    Secondary
    End point timeframe
    Any use of renal replacement therapy after randomisation
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1853
    1860
    Units: number
        Yes
    567
    609
    Statistical analysis title
    		 Logistic regression model with random effect
    Statistical analysis description
    The secondary outcome is presented as the odds ratio (OR) and the corresponding 95% confidence intervals (CI), analyzed using a logistic regression adjusted for stratification variables with medical vs. surgical diagnosis as a fixed effect and site as a random effect.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    3713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.03
    Variability estimate
    Standard error of the mean

    Secondary: New bactermia of fungermia

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    End point title
    		 New bactermia of fungermia
    End point description
    End point type
    Secondary
    End point timeframe
    New bactermia of fungermia after randomisation
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1853
    1860
    Units: number
        Yes
    262
    262
    Statistical analysis title
    		 Logistic regression model with random effect
    Statistical analysis description
    The secondary outcome is presented as the odds ratio (OR) and the corresponding 95% confidence intervals (CI), analyzed using a logistic regression adjusted for stratification variables with medical vs. surgical diagnosis as a fixed effect and site as a random effect.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    3713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.16
    Variability estimate
    Standard error of the mean

    Secondary: Blood transfusion

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    End point title
    		 Blood transfusion
    End point description
    End point type
    Secondary
    End point timeframe
    Any blood transfusion after randomisation
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1848
    1855
    Units: number
        Yes
    683
    773
    Statistical analysis title
    		 Logistic regression model with random effect
    Statistical analysis description
    Statistical analysis description The secondary outcome is presented as the odds ratio (OR) and the corresponding 95% confidence intervals (CI), analyzed using a logistic regression adjusted for stratification variables with medical vs. surgical diagnosis as a fixed effect and site as a random effect.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    3703
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 0.94
    Variability estimate
    Standard error of the mean

    Secondary: Days alive and free of ICU

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    End point title
    		 Days alive and free of ICU
    End point description
    End point type
    Secondary
    End point timeframe
    Days alive and free of ICU after randomisation
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1853
    1860
    Units: day
        arithmetic mean (standard deviation)
    58.2 ( 34.8 )
    56.0 ( 35.4 )
    Statistical analysis title
    		 Generalized linear regression model with random ef
    Statistical analysis description
    The secondary outcome is presented as the mean difference and the corresponding95% confidence intervals (CI), analyzed using a linear regression adjusted for stratification variables with medical vs. surgical diagnosis as a fixed effect and site as a random effect.
    Comparison groups
    Placebo v Hydrocortisone
    Number of subjects included in analysis
    3713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Generalised linear model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 4.49
    Variability estimate
    Standard error of the mean

    Secondary: Days alive and free of hospital

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    End point title
    		 Days alive and free of hospital
    End point description
    End point type
    Secondary
    End point timeframe
    Days alive and free of hospital after randomisation
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1853
    1860
    Units: day
        arithmetic mean (standard deviation)
    40.0 ( 32.0 )
    38.6 ( 32.4 )
    Statistical analysis title
    		 Generalized linear regression model with random ef
    Statistical analysis description
    Generalized linear regression model with random effect. The secondary outcome is presented as the mean difference and the corresponding 95% confidence intervals (CI), analyzed using a linear regression adjusted for stratification variables with medical vs. surgical diagnosis as a fixed effect and site as a random effect.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    3713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Generalised linear model
    Parameter type
    		 Median difference (final values)
    Point estimate
    1.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 3.49
    Variability estimate
    Standard error of the mean

    Secondary: Days alive and free of mechanical ventilation

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    End point title
    		 Days alive and free of mechanical ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    Days alive and free of mechanical ventilation after randomisation
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1853
    1860
    Units: day
        arithmetic mean (standard deviation)
    61.2 ( 35.6 )
    59.1 ( 36.1 )
    Statistical analysis title
    		 Generalized linear regression model with random ef
    Statistical analysis description
    The secondary outcome is presented as the mean difference and the corresponding 95% confidence intervals (CI), analyzed using a linear regression adjusted for stratification variables with medical vs. surgical diagnosis as a fixed effect and site as a random effect.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    3713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Generalised linear model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 4.46
    Variability estimate
    Standard error of the mean

    Secondary: Days alive and free of RRT

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    End point title
    		 Days alive and free of RRT
    End point description
    End point type
    Secondary
    End point timeframe
    Days alive and free of renal replacement therapy after randomisation
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1853
    1860
    Units: day
        arithmetic mean (standard deviation)
    42.6 ( 39.1 )
    40.4 ( 38.5 )
    Statistical analysis title
    		 Generalized linear regression model with random ef
    Statistical analysis description
    Generalized linear regression model with random effect. The secondary outcome is presented as the mean difference and the corresponding 95% confidence intervals (CI), analyzed using a linear regression adjusted for stratification variables with medical vs. surgical diagnosis as a fixed effect and site as a random effect.
    Comparison groups
    Placebo v Hydrocortisone
    Number of subjects included in analysis
    3713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Generalised linear model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 6.75
    Variability estimate
    Standard error of the mean

    Secondary: Time to reversal of shock

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    End point title
    		 Time to reversal of shock
    End point description
    End point type
    Secondary
    End point timeframe
    Time to first shock reversal in days
    End point values
    		 Hydrocortisone Placebo
    Number of subjects analysed
    1843
    1854
    Units: day
    number (not applicable)
        Yes
    1634
    1574
    Statistical analysis title
    		 Cox regression model with random effect
    Statistical analysis description
    Time to event analysis was done using a Cox proportional hazard model including the randomized treatment arm, admission type and a random-center effect. Time-to-resolution were analyzed both by treating death as a competing risk and described using cumulative incidence function
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    3697
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Frailty regression model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.23
         upper limit
    		 1.41
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the randomisation date to end of the 90th day from randomisation.
    Adverse event reporting additional description
    Adverse Event form that is completed by the site and submitted to the Sponsor at the time of recognition of an adverse event.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 TGA Definition
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Hydrocortisone
    Reporting group description
    		 Hydrocortisone arm. Deaths were not recorded as a Serious Adverse Event as they were the primary outcome of the study.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm. Deaths were not recorded as a Serious Adverse Event as they were the primary outcome of the study.

    Serious adverse events
    		 Hydrocortisone Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 1853 (0.22%)
    2 / 1860 (0.11%)
         number of deaths (all causes)
    511
    526
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Abdominal-wound dehiscence
         subjects affected / exposed
    0 / 1853 (0.00%)
    1 / 1860 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myopathy
         subjects affected / exposed
    1 / 1853 (0.05%)
    0 / 1860 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory Shock
         subjects affected / exposed
    1 / 1853 (0.05%)
    0 / 1860 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Bleeding
         subjects affected / exposed
    0 / 1853 (0.00%)
    1 / 1860 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ischemic bowel
         subjects affected / exposed
    1 / 1853 (0.05%)
    0 / 1860 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Hydrocortisone Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 1853 (0.92%)
    4 / 1860 (0.22%)
    Blood and lymphatic system disorders
    Hypernatraemia
         subjects affected / exposed
    3 / 1853 (0.16%)
    0 / 1860 (0.00%)
         occurrences all number
    3
    0
    Hyperchloraemia
         subjects affected / exposed
    1 / 1853 (0.05%)
    0 / 1860 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    3 / 1853 (0.16%)
    0 / 1860 (0.00%)
         occurrences all number
    0
    0
    Bleeding
         subjects affected / exposed
    2 / 1853 (0.11%)
    0 / 1860 (0.00%)
         occurrences all number
    0
    0
    Leukocytosis
         subjects affected / exposed
    2 / 1853 (0.11%)
    0 / 1860 (0.00%)
         occurrences all number
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 1853 (0.05%)
    0 / 1860 (0.00%)
         occurrences all number
    0
    0
    General disorders and administration site conditions
    Encephalopathy
         subjects affected / exposed
    3 / 1853 (0.16%)
    0 / 1860 (0.00%)
         occurrences all number
    0
    0
    Miscellaneous
         subjects affected / exposed
    0 / 1853 (0.00%)
    1 / 1860 (0.05%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hyperglycaemia
         subjects affected / exposed
    6 / 1853 (0.32%)
    3 / 1860 (0.16%)
         occurrences all number
    6
    3
    Infections and infestations
    Septic arthritis
         subjects affected / exposed
    1 / 1853 (0.05%)
    0 / 1860 (0.00%)
         occurrences all number
    1
    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29347874
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