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    Clinical Trial Results:
    Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: The COVID STEROID randomised, placebo-controlled trial

    Summary
    EudraCT number
    2020-001395-15
    Trial protocol
    DK  
    Global end of trial date
    12 Jun 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Jul 2022
    First version publication date
    22 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    v. 2.1, date 12.05.2020
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04348305
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Department of Intensive Care, Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    Prof. Anders Perner, Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet, Denmark, +45 35458333, contact@cric.nu
    Scientific contact
    Prof. Anders Perner, Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet, Denmark, +45 35458333, contact@cric.nu
    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
    14 Oct 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess benefits and harms of low dose IV hydrocortisone versus placebo on patient-important outcome measures in adult patients with COVID-19 and severe hypoxia.
    Protection of trial subjects
    Patients with COVID-19 and severe hypoxia are at high risk of death. When this trial was initiated, there was no proven treatment for COVID-19; the care was only supportive, including respiratory and circulatory support. For other patient groups with similar critical illnesses, lower dose corticosteroids were used because they mitigate critical illness and potentially also mortality without serious adverse reactions. Therefore, there was reason to believe that similar positive effects could be obtained in patients with COVID-19 and severe hypoxia without serious adverse reactions. The trial was conducted to the highest of methodological standards with ongoing assessment of the known serious adverse reactions to corticosteroid and three planned interim analyses. The control group received placebo and best clinical care without corticosteroids as was recommended for these patients in Denmark at that time. The trial was ended prematurely due to the results from a WHO-initiated prospective meta-analysis of ongoing or recently completed trials demonstrating benefit from systemic corticosteroids on 28-day mortality in critically ill patients with COVID-19, which in turn led to an update in the guideline from the WHO strongly recommending the use of systemic corticosteroids for patients with severe or critical COVID-19.
    Background therapy
    All other treatments than the trial drug were at the discretion of the treating clinicians.
    Evidence for comparator
    Placebo
    Actual start date of recruitment
    15 Apr 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    19
    From 65 to 84 years
    8
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    We recruited patients from 15 April 2020 to 16 June 2020.

    Pre-assignment
    Screening details
    We screened adult patients (18 years or above) with confirmed SARS-CoV-2 infection and severe hypoxia (i.e., use of invasive mechanical ventilation, NIV, or continuous use of CPAP for hypoxia, or oxygen supplementation with an oxygen flow of at least 10 L/min). We screened 67, excluded 37, and randomised 30 patients.

    Period 1
    Period 1 title
    Intervention period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The Management Committee, investigators, trial site staff registering outcome data, trial statistician, clinical staff, relatives, and patients were all blinded to the allocation. Trial medication was prepared daily using shelf-medication by unblinded staff (medical students and/or research nurses and doctors). The unblinded staff were not involved in the care of patients, outcome data entry, or statistical analyses.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Hydrocortisone
    Arm description
    Intravenous hydrocortisone 200 mg per day for 7 days
    Arm type
    Experimental

    Investigational medicinal product name
    Hydrocortisone
    Investigational medicinal product code
    H02AB09
    Other name
    Solu-Cortef
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/day given as continuous infusion over 24 hours or bolus injection (50 mg per bolus) every 6 hours.

    Arm title
    Placebo
    Arm description
    Isotonic saline for 7 days
    Arm type
    Placebo

    Investigational medicinal product name
    Sodium Chloride
    Investigational medicinal product code
    B05BB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Continuous infusion over 24 hours or as bolus injections every 6 hours for 7 days.

    Number of subjects in period 1
    Hydrocortisone Placebo
    Started
    16
    14
    Completed
    14
    13
    Not completed
    2
    1
         Physician decision
    1
    -
         Withdrew from active therapy
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Hydrocortisone
    Reporting group description
    Intravenous hydrocortisone 200 mg per day for 7 days

    Reporting group title
    Placebo
    Reporting group description
    Isotonic saline for 7 days

    Reporting group values
    Hydrocortisone Placebo Total
    Number of subjects
    16 14 30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    11 8 19
        From 65-84 years
    4 4 8
        85 years and over
    1 2 3
        Not recorded
    0 0 0
    Age continuous
    Age in years at the time of randomisation
    Units: years
        median (inter-quartile range (Q1-Q3))
    59 (52 to 74) 62 (55 to 71) -
    Gender categorical
    Units: Subjects
        Female
    2 4 6
        Male
    14 10 24

    End points

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    End points reporting groups
    Reporting group title
    Hydrocortisone
    Reporting group description
    Intravenous hydrocortisone 200 mg per day for 7 days

    Reporting group title
    Placebo
    Reporting group description
    Isotonic saline for 7 days

    Primary: Days alive without life support at day 28

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    End point title
    Days alive without life support at day 28
    End point description
    Days alive without the use of life support (i.e., invasive mechanical ventilation, circulatory support, or renal replacement therapy, including days in between intermittent renal replacementtherapy)
    End point type
    Primary
    End point timeframe
    From randomisation to day 28.
    End point values
    Hydrocortisone Placebo
    Number of subjects analysed
    16
    14
    Units: Days
        median (inter-quartile range (Q1-Q3))
    7 (2 to 24)
    10 (3 to 26)
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Linear regression adjusted for invasive mechanical ventilation and age below 70 years. We were unable to adjust for site due to the reduced sample size.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    superiority [1]
    P-value
    = 0.79
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.5
         upper limit
    7.3
    Notes
    [1] - We had to conduct another statistical analysis than the pre-planned due to the reduced sample size.

    Secondary: Number of patients with one or more serious adverse reactions at day 14

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    End point title
    Number of patients with one or more serious adverse reactions at day 14
    End point description
    Number of patients with one or more serious adverse reactions (i.e., new episodes of septic shock, invasive fungal infection, clinically important gastrointestinal bleeding, or anaphylactic reaction).
    End point type
    Secondary
    End point timeframe
    From randomisation to day 14
    End point values
    Hydrocortisone Placebo
    Number of subjects analysed
    16
    14
    Units: Number
    1
    0
    Statistical analysis title
    Primary analysis
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1
    Method
    Fisher exact
    Confidence interval

    Secondary: All-cause mortality at day 28

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    End point title
    All-cause mortality at day 28
    End point description
    All-cause mortality
    End point type
    Secondary
    End point timeframe
    From randomisation to day 28
    End point values
    Hydrocortisone Placebo
    Number of subjects analysed
    16
    14
    Units: Number
    6
    2
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Unadjusted generalised linear model with log link and binomial error distribution
    Comparison groups
    Placebo v Hydrocortisone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.19
    Method
    GLM log link/binomial error distrib.
    Parameter type
    Risk ratio (RR)
    Point estimate
    2.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.74
         upper limit
    16.03

    Secondary: All-cause mortality at day 90

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    End point title
    All-cause mortality at day 90
    End point description
    All-cause mortality
    End point type
    Secondary
    End point timeframe
    From randomisation to day 90
    End point values
    Hydrocortisone Placebo
    Number of subjects analysed
    16
    14
    Units: Number
    7
    3
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Unadjusted generalised linear model with log link and binomial error distribution.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.22
    Method
    GLM log link/binomial error distrib.
    Parameter type
    Risk ratio (RR)
    Point estimate
    2.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    8.16

    Secondary: Days alive without life support at day 90

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    End point title
    Days alive without life support at day 90
    End point description
    Days alive without the use of life support (i.e., invasive mechanical ventilation, circulatory support, or renal replacement therapy, including days in between intermittent renal replacement therapy)
    End point type
    Secondary
    End point timeframe
    From randomisation to day 90
    End point values
    Hydrocortisone Placebo
    Number of subjects analysed
    16
    14
    Units: Days
        median (inter-quartile range (Q1-Q3))
    41 (6 to 86)
    72 (52 to 88)
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Linear regression adjusted for invasive mechanical ventilation (y/n) and age below 70 (y/n).
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.25
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -14.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40.4
         upper limit
    10.9

    Secondary: Days alive and out of hospital at day 90

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    End point title
    Days alive and out of hospital at day 90
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to day 90.
    End point values
    Hydrocortisone Placebo
    Number of subjects analysed
    16
    14
    Units: Days
        median (inter-quartile range (Q1-Q3))
    31 (8 to 78)
    53 (42 to 68)
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Linear regression adjusted for invasive mechanical ventilation (y/n) and age below 70 (y/n).
    Comparison groups
    Placebo v Hydrocortisone
    Number of subjects included in analysis
    30
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.57
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29.6
         upper limit
    16.7

    Secondary: All-cause mortality at 1 year

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    End point title
    All-cause mortality at 1 year
    End point description
    All-cause mortality
    End point type
    Secondary
    End point timeframe
    From randomisation to 1 year.
    End point values
    Hydrocortisone Placebo
    Number of subjects analysed
    16
    14
    Units: Number
    8
    3
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Unadjusted generalised linear model with log link and binomial error distribution.
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14
    Method
    GLM log link/binomial error distrib.
    Parameter type
    Risk ratio (RR)
    Point estimate
    2.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    9.17

    Secondary: EQ-VAS

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    End point title
    EQ-VAS
    End point description
    Health-related quality of life assessed by EQ-VAS
    End point type
    Secondary
    End point timeframe
    At 1 year
    End point values
    Hydrocortisone Placebo
    Number of subjects analysed
    16
    11
    Units: mm
        median (inter-quartile range (Q1-Q3))
    27.5 (0.0 to 75.0)
    60.0 (15.0 to 67.5)
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    EQ-VAS ranges from 0-100 mm. Analysed using a linear regression adjusted for invasive mechanical ventilation (y/n) and age below 70 years (y/n).
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    27
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.61
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -38.5
         upper limit
    23

    Secondary: EQ-5D-5L index value

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    End point title
    EQ-5D-5L index value
    End point description
    EQ-5D-5L index value are anchored at 1 (perfect health) and 0 (health state as bad as being dead) with negative values representing health states worse than death.
    End point type
    Secondary
    End point timeframe
    At 1 year.
    End point values
    Hydrocortisone Placebo
    Number of subjects analysed
    16
    11
    Units: Index value
        median (inter-quartile range (Q1-Q3))
    0.3 (0.0 to 0.9)
    0.6 (0.2 to 0.8)
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Analysed using a linear regression adjusted for invasive mechanical ventilation (y/n) and age below 70 years (y/n).
    Comparison groups
    Hydrocortisone v Placebo
    Number of subjects included in analysis
    27
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.61
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.43
         upper limit
    0.25

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From randomisation to day 14.
    Adverse event reporting additional description
    Serious adverse reactions were a predefined outcome in the trial. The following SARs occured in the two reporting groups: Hydrocortisone: septic shock 1/16 Placebo: septic shock 0/14
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: We only recorded serious adverse reactions and serious adverse events in the trial. No non-serious adverse events were recorded, but the patient charts contain daily registrations of clinical data, which can be obtained on request from the medical authorities.

    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? Yes
    Date
    Interruption
    Restart date
    16 Jun 2020
    Enrolment paused due to external evidence reporting benefit from systemic corticosteroids on 28-day mortality in hospitalised patients with COVID-19
    03 Sep 2020
    03 Sep 2020
    Enrolment terminated due to update in the guideline from the WHO strongly recommending systemic corticosteroids for patients with severe or critical COVID-19
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Highly uncertain results due to the reduced sample size (3% of the planned sample size).

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/34138478
    http://www.ncbi.nlm.nih.gov/pubmed/35067914
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