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    Clinical Trial Results:
    Higher vs. Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia: the COVID STEROID 2 trial

    Summary
    EudraCT number
    2020-003363-25
    Trial protocol
    DK  
    Global end of trial date
    16 Nov 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. 1.9, date 27.01.2021
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04509973
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Department of Intensive Care, Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    Anders Perner, Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet, Denmark, +45 35458333, anders.perner@regionh.dk
    Scientific contact
    Anders Perner, Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet, Denmark, +45 35458333, 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
    01 Feb 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effects of higher (12 mg) vs lower doses (6 mg) of intravenous dexamethasone on the number of days alive without life-support in adult patients with COVID-19 and severe hypoxia.
    Protection of trial subjects
    The RECOVERY trial (doi: 10.1056/NEJMoa2021436) reported a reduction in 28-day mortality with low-dose dexamethasone (6 mg) for hospitalised patients with suspected or confirmed COVID-19. Yet, higher doses were used in the other trials of corticosteroids in COVID-19 (median dose 12 mg). We surveyed 278 doctors at COVID STEROID 2 trial sites on their clinical preferences for corticosteroid use in patients with COVID-19. The dose preference varied with 56% of 240 responders preferring a dose of 6 mg of dexamethasone or equivalent, and 36% of 240 responders preferring doses higher than 6 mg of dexamethasone or equivalent (doi: 10.1111/aas.13941). Most would enrol patients in a future trial comparing a higher vs lower dose of dexamethasone, primarily into one comparing 12 mg vs 6 mg of dexamethasone (55% of 237 responders) (doi: 10.1111/aas.13941). Taken together, it was unclear which dose of dexamethasone was most beneficial to COVID-19, and clinical equipoise existed among clinicians and researchers. The trial was conducted to the highest of methodological standards with ongoing assessment of the known serious adverse reactions to corticosteroid, including a planned interim analysis. Any serious adverse reactions for single participants and the group of participants receiving higher vs. lower dose of dexamethasone was assessed and handled.
    Background therapy
    All other treatments than the trial drug were at the discretion of the treating clinicians.
    Evidence for comparator
    The control group received the exact same protocol as in the RECOVERY trial (i.e., 6 mg of dexamethasone daily for 10 days) in addition to usual clinical care.
    Actual start date of recruitment
    27 Aug 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 79
    Country: Number of subjects enrolled
    Denmark: 485
    Country: Number of subjects enrolled
    India: 369
    Country: Number of subjects enrolled
    Switzerland: 49
    Worldwide total number of subjects
    982
    EEA total number of subjects
    564
    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)
    491
    From 65 to 84 years
    471
    85 years and over
    20

    Subject disposition

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    Recruitment
    Recruitment details
    We recruited patients from 27 August 2020 to 20 May 2021.

    Pre-assignment
    Screening details
    We screened adult patients (18 years or above) with confirmed SARS-CoV-2 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 1414, excluded 414, randomised 1000, and included 982 patients in the analyses.

    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
    12 mg of dexamethasone
    Arm description
    12 mg of dexamethasone (14.4 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation.
    Arm type
    Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    H02AB02
    Other name
    Dexavit
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    12 mg per day as bolus injection once daily for up to 10 days after randomisation. Used at all sites but one Swedish site that used betamethasone instead.

    Investigational medicinal product name
    Betamethasone
    Investigational medicinal product code
    H02AB02
    Other name
    Betapred
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    12 mg of betamethasone as bolus injection once daily for up to 10 days after randomisation. Only used at one Swedish site, where dexamethasone was not available.

    Arm title
    6 mg of dexamethasone
    Arm description
    6 mg of dexamethasone (7.2 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation.
    Arm type
    Active comparator

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    H02AB02
    Other name
    Dexavit
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg per day as bolus injection once daily for up to 10 days after randomisation. Used at all sites but one Swedish site that used betamethasone instead.

    Investigational medicinal product name
    Betamethasone
    Investigational medicinal product code
    H02AB02
    Other name
    Betapred
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg of betamethasone as bolus injection once daily for up to 10 days after randomisation. Only used at one Swedish site, where dexamethasone was not available.

    Number of subjects in period 1
    12 mg of dexamethasone 6 mg of dexamethasone
    Started
    497
    485
    Completed
    461
    446
    Not completed
    36
    39
         Protocol deviation
    36
    39

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    12 mg of dexamethasone
    Reporting group description
    12 mg of dexamethasone (14.4 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation.

    Reporting group title
    6 mg of dexamethasone
    Reporting group description
    6 mg of dexamethasone (7.2 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation.

    Reporting group values
    12 mg of dexamethasone 6 mg of dexamethasone Total
    Number of subjects
    497 485 982
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    248 243 491
        From 65-84 years
    239 232 471
        85 years and over
    10 10 20
        Not reported
    0 0 0
    Age continuous
    Age at the time of randomisation.
    Units: years
        median (inter-quartile range (Q1-Q3))
    65 (56 to 74) 64 (54 to 72) -
    Gender categorical
    Units: Subjects
        Female
    151 154 305
        Male
    346 331 677

    End points

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    End points reporting groups
    Reporting group title
    12 mg of dexamethasone
    Reporting group description
    12 mg of dexamethasone (14.4 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation.

    Reporting group title
    6 mg of dexamethasone
    Reporting group description
    6 mg of dexamethasone (7.2 mg dexamethasone phosphate) suspended in sodium chloride 0.9% and administered as a masked bolus injection (5 mL) intravenously once daily for up to 10 days from randomisation.

    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 replacement therapy).
    End point type
    Primary
    End point timeframe
    From randomisation to day 28.
    End point values
    12 mg of dexamethasone 6 mg of dexamethasone
    Number of subjects analysed
    491
    480
    Units: Days
        median (inter-quartile range (Q1-Q3))
    22.0 (6.0 to 28.0)
    20.5 (4.0 to 28.0)
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    P-value calculated using the Kryger Jensen and Lange test adjusted for stratification variables (site, age younger than 70 years, and use of invasive mechanical ventilation). The mean difference and confidence interval were calculated using an adjusted linear regression and bootstrapping with 50,000 resamples.
    Comparison groups
    12 mg of dexamethasone v 6 mg of dexamethasone
    Number of subjects included in analysis
    971
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.07
    Method
    Kryger Jensen and Lange test
    Parameter type
    Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    2.6

    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
    12 mg of dexamethasone 6 mg of dexamethasone
    Number of subjects analysed
    489
    478
    Units: Days
        median (inter-quartile range (Q1-Q3))
    84.0 (9.3 to 90.0)
    80.0 (6.0 to 90.0)
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    P-value calculated using the Kryger Jensen and Lange test adjusted for stratification variables (site, age younger than 70 years, and use of invasive mechanical ventilation). The mean difference and confidence interval were calculated using an adjusted linear regression and bootstrapping with 50,000 resamples.
    Comparison groups
    12 mg of dexamethasone v 6 mg of dexamethasone
    Number of subjects included in analysis
    967
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.15
    Method
    Kryger Jensen and Lange test
    Parameter type
    Mean difference (final values)
    Point estimate
    4.4
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    10.4

    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
    12 mg of dexamethasone 6 mg of dexamethasone
    Number of subjects analysed
    490
    478
    Units: Days
        median (inter-quartile range (Q1-Q3))
    61.5 (0.0 to 78.0)
    48.0 (0.0 to 76.0)
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    P-value calculated using the Kryger Jensen and Lange test adjusted for stratification variables (site, age younger than 70 years, and use of invasive mechanical ventilation). The mean difference and confidence interval were calculated using an adjusted linear regression and bootstrapping with 50,000 resamples.
    Comparison groups
    12 mg of dexamethasone v 6 mg of dexamethasone
    Number of subjects included in analysis
    968
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.09
    Method
    Kryger Jensen and Lange test
    Parameter type
    Mean difference (final values)
    Point estimate
    4.1
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    9.5

    Secondary: Mortality at day 28

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    End point title
    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
    12 mg of dexamethasone 6 mg of dexamethasone
    Number of subjects analysed
    491
    480
    Units: Number
    133
    155
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Logistic regression adjusted for the stratification variables and g-computation.
    Comparison groups
    12 mg of dexamethasone v 6 mg of dexamethasone
    Number of subjects included in analysis
    971
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.1
    Method
    Regression, Logistic
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.86
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    1.08

    Secondary: Mortality at day 90

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    End point title
    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
    12 mg of dexamethasone 6 mg of dexamethasone
    Number of subjects analysed
    490
    478
    Units: Number
    157
    180
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Logistic regression adjusted for the stratification variables and g-computation.
    Comparison groups
    12 mg of dexamethasone v 6 mg of dexamethasone
    Number of subjects included in analysis
    968
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.09
    Method
    Regression, Logistic
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.87
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.07

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

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    End point title
    Number of patients with one or more serious adverse reactions
    End point description
    The number of patients with 1 or more serious adverse reactions (i.e., new episodes of septic shock, invasive fungal infection, clinically important gastrointestinal bleeding, or anaphylactic reaction to dexamethasone).
    End point type
    Secondary
    End point timeframe
    From randomisation to day 28
    End point values
    12 mg of dexamethasone 6 mg of dexamethasone
    Number of subjects analysed
    497
    485
    Units: Number
    56
    65
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Logistic regression adjusted for the stratification variables and g-computation.
    Comparison groups
    12 mg of dexamethasone v 6 mg of dexamethasone
    Number of subjects included in analysis
    982
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.27
    Method
    Regression, Logistic
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.83
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.29

    Secondary: Mortality at day 180

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    End point title
    Mortality at day 180
    End point description
    All-cause mortality
    End point type
    Secondary
    End point timeframe
    From randomisation to day 180.
    End point values
    12 mg of dexamethasone 6 mg of dexamethasone
    Number of subjects analysed
    486
    477
    Units: Number
    164
    184
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Logistic regression adjusted for the stratification variables and g-computation.
    Comparison groups
    12 mg of dexamethasone v 6 mg of dexamethasone
    Number of subjects included in analysis
    963
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.13
    Method
    Regression, Logistic
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.89
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.09

    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 day 180.
    End point values
    12 mg of dexamethasone 6 mg of dexamethasone
    Number of subjects analysed
    497
    485
    Units: mm
        median (inter-quartile range (Q1-Q3))
    65 (0 to 90)
    55 (0 to 85)
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    P-value calculated using the Kryger Jensen and Lange test adjusted for stratification variables (site, age younger than 70 years, and use of invasive mechanical ventilation). The mean difference and confidence interval were calculated using an adjusted linear regression and bootstrapping with 50,000 resamples. Non-survivors were assigned the worst possible value (i.e., 0 mm). Data from non-responders were multiply imputed (n = 58).
    Comparison groups
    12 mg of dexamethasone v 6 mg of dexamethasone
    Number of subjects included in analysis
    982
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.22
    Method
    Kryger Jensen and Lange test
    Parameter type
    Mean difference (final values)
    Point estimate
    4
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -3
         upper limit
    10

    Secondary: EQ-5D-5L index value

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    End point title
    EQ-5D-5L index value
    End point description
    Health-related quality of life assessed by the EQ-5D-5L index values.
    End point type
    Secondary
    End point timeframe
    At day 180.
    End point values
    12 mg of dexamethasone 6 mg of dexamethasone
    Number of subjects analysed
    497
    485
    Units: Index value
        median (inter-quartile range (Q1-Q3))
    0.80 (0.0 to 0.97)
    0.68 (0.0 to 0.95)
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    P-value calculated using the Kryger Jensen and Lange test adjusted for stratification variables (site, age younger than 70 years, and use of invasive mechanical ventilation). The mean difference and confidence interval were calculated using an adjusted linear regression and bootstrapping with 50,000 resamples. Non-survivors were assigned scores of zero corresponding to a health state equivalent to death for EQ-5D-5L index values. Data from non-responders were multiply imputed (n = 60).
    Comparison groups
    12 mg of dexamethasone v 6 mg of dexamethasone
    Number of subjects included in analysis
    982
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1
    Method
    Kryger Jensen and Lange test
    Parameter type
    Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    99%
         sides
    2-sided
         lower limit
    -4
         upper limit
    4

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From randomisation to day 28.
    Adverse event reporting additional description
    For SARs and SAEs, refer to Table 2 and Supplement 2, eTable 10. Link: https://jamanetwork.com/journals/jama/fullarticle/2785529?utm_campaign=articlePDF&utm_medium=articlePDFlink&utm_source=articlePDF&utm_content=jama.2021.18295
    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? Yes
    Date
    Amendment
    09 Jan 2021
    We generally recommended against the use of other immunosuppresive agents during the intervention period. However, after 9 January 2021, we allowed the use of interleukin 6 (IL-6) inhibitors after the publications of the results from the IL-6 inhibitor domain of the REMAP-CAP trial (doi: 10.1056/NEJMoa2100433).

    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.
    Changes in the treatment of COVID-19 during the course of the trial. Intervention period varied from 6-10 days according to the number of days of steroid treatment before randomisation (max 4 days allowed). Both may have influenced the trial results.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/34673895
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