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    Clinical Trial Results:
    USE OF GLUCOCORTICOIDS IN PATIENTS WITH SARS-COV-2 CORONAVIRUS INFECTION. Pragmatic trial inserted in real practice during a pandemic.

    Summary
    EudraCT number
    		 2020-005026-28
    Trial protocol
    		 ES  
    Global end of trial date
    09 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jan 2023
    First version publication date
    08 Jan 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GLUCOCOVID-bolus
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04780581
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fundación IECSCYL-IBSAL.
    Sponsor organisation address
    Hospital Universitario de Salamanca Edificio Virgen de la Vega, 10.ª planta Pº San Vicente, 55-182, Salamanca, Spain, 37007
    Public contact
    Clinical Trial Area, IBSAL, 34 9232911005779, esperanza.lopez@scren.es
    Scientific contact
    Clinical Trial Area, IBSAL, 34 9232911005779, esperanza.lopez@scren.es
    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
    19 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Nov 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of high-dose methylprednisolone bolus administration against the intermediate-dose dexamethasone pattern (RECOVERY trial) in COVID-19 patients with non-critical respiratory failure.
    Protection of trial subjects
    Adequate information of each patient and efficient monitoring of treatment safety through pharmacovigilance.
    Background therapy
    		 Standard of therapy for severe SARS-CoV-2 infection.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Dec 2020
    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
    Spain: 125
    Worldwide total number of subjects
    125
    EEA total number of subjects
    125
    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)
    74
    From 65 to 84 years
    46
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible patients were those aged 18 years or older, hospitalized with confirmed SARS-CoV-2 infection, with evidence of pulmonary involvement in radiology, and who required supplementary oxygen

    Pre-assignment
    Screening details
    		 Patient were excluded if the patient's situation is so serious that the doctor in charge thinks he could die within 24 hours, patients require one of the following 4 ventilatory supports at the time of randomisation.

    Period 1
    Period 1 title
    Completed (28 d)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 250 mg methylprednisolone
    Arm description
    		 High dose GC
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    H02AB04
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in cartridge
    Routes of administration
    Intravenous use
    Dosage and administration details
    Daily intravenous pulse with methylprednisolone 250 mg (equivalence to 46.9 mg of dexamethasone) for 3 days. There was no placebo from days 4 to 10 for patients in the methylprednisolone group.

    Arm title
    		 6 mg dexamethasone
    Arm description
    		 RECOVERY trial
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    H02AB02
    Other name
    Pharmaceutical forms
    Suspension for oral suspension, Tablet
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    daily dose of 6 mg of dexamethasone (equivalence to 32 mg of methylprednisolone) for up to 10 days. For the dexamethasone group, the first 3 days of treatment were intravenous (7.2 mg of dexamethasone phosphate).

    Number of subjects in period 1
    		250 mg methylprednisolone 6 mg dexamethasone
    Started
    63
    62
    Completed
    63
    62
    Period 2
    Period 2 title
    Completed (90 d)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Centralized, web based (https://www.sharecrf.com/)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 250 mg methylprednisolone
    Arm description
    		 High dose GC
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    H02AB04
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in cartridge
    Routes of administration
    Intravenous use
    Dosage and administration details
    Daily intravenous pulse with methylprednisolone 250 mg (equivalence to 46.9 mg of dexamethasone) for 3 days. There was no placebo from days 4 to 10 for patients in the methylprednisolone group.

    Arm title
    		 6 mg dexamethasone
    Arm description
    		 RECOVERY trial
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    H02AB02
    Other name
    Pharmaceutical forms
    Suspension for oral suspension, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    daily dose of 6 mg of dexamethasone (equivalence to 32 mg of methylprednisolone) for up to 10 days. For the dexamethasone group, the first 3 days of treatment were intravenous (7.2 mg of dexamethasone phosphate).

    Number of subjects in period 2
    		250 mg methylprednisolone 6 mg dexamethasone
    Started
    63
    62
    Completed
    63
    60
    Not completed
    0
    2
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    250 mg methylprednisolone
    Reporting group description
    		 High dose GC

    Reporting group title
    6 mg dexamethasone
    Reporting group description
    		 RECOVERY trial

    Reporting group values
    		 250 mg methylprednisolone 6 mg dexamethasone Total
    Number of subjects
    		 63 62 125
    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)
    		 37 37 74
        From 65-84 years
    		 23 23 46
        85 years and over
    		 3 2 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.81 ± 16.90 58.73 ± 16.01 -
    Gender categorical
    Units: Subjects
        Female
    		 20 21 41
        Male
    		 43 41 84
    Subject analysis sets

    Subject analysis set title
    Intention to treat patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat patients

    Subject analysis sets values
    		 Intention to treat patients
    Number of subjects
    125
    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)
    74
        From 65-84 years
    46
        85 years and over
    5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.27 ± 16.41
    Gender categorical
    Units: Subjects
        Female
    41
        Male
    84

    End points

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    End points reporting groups
    Reporting group title
    250 mg methylprednisolone
    Reporting group description
    		 High dose GC

    Reporting group title
    6 mg dexamethasone
    Reporting group description
    		 RECOVERY trial
    Reporting group title
    250 mg methylprednisolone
    Reporting group description
    		 High dose GC

    Reporting group title
    6 mg dexamethasone
    Reporting group description
    		 RECOVERY trial

    Subject analysis set title
    Intention to treat patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat patients

    Primary: Mortality within 28 d

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    End point title
    		 Mortality within 28 d
    End point description
    End point type
    Primary
    End point timeframe
    28 days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    63
    62
    Units: subjects
    3
    3
    Statistical analysis title
    		 Primary outcome of 28-day mortality
    Statistical analysis description
    For the primary outcome of 28-day mortality, we used the log-rank statistic to test the null hypothesis of equal survival curves. Time-to-event secondary outcomes and the composite outcome were compared between the two groups with the Kaplan–Meier approach.
    Comparison groups
    250 mg methylprednisolone v 6 mg dexamethasone
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 ≤ 0.05
    Method
    		 Logrank
    Parameter type
    		 Log risk ratio
    Confidence interval
    Notes
    [1] - log-rank statistic

    Secondary: Admission to intensive care unit within 28 d

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    End point title
    		 Admission to intensive care unit within 28 d
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    60
    62
    Units: subjects
    10
    9
    No statistical analyses for this end point

    Secondary: Tracheal intubation within 28d

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    End point title
    		 Tracheal intubation within 28d
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    63
    62
    Units: subjects
    8
    7
    No statistical analyses for this end point

    Secondary: Non-invasive respiratory support within 28d

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    End point title
    		 Non-invasive respiratory support within 28d
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    63
    62
    Units: subjects
    3
    2
    No statistical analyses for this end point

    Secondary: High-flow oxygen support within 28d

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    End point title
    		 High-flow oxygen support within 28d
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    63
    62
    Units: subjects
    6
    8
    No statistical analyses for this end point

    Secondary: Additional immunosuppressive drugs within 28d

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    End point title
    		 Additional immunosuppressive drugs within 28d
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    63
    62
    Units: subjects
    14
    14
    No statistical analyses for this end point

    Secondary: Length of stay

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    End point title
    		 Length of stay
    End point description
    End point type
    Secondary
    End point timeframe
    28 Days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    63
    62
    Units: day
        arithmetic mean (standard deviation)
    13 ± 15
    13 ± 12
    No statistical analyses for this end point

    Secondary: Mortality within 90 d

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    End point title
    		 Mortality within 90 d
    End point description
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    63
    60
    Units: subjects
    6
    4
    No statistical analyses for this end point

    Secondary: Clinical evaluation of patient status according to the WHO 10-category scale

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    End point title
    		 Clinical evaluation of patient status according to the WHO 10-category scale
    End point description
    Clinical evaluation of patient status according to the WHO 10-category scale. Minimum value: 1 and maximum value: 10, higher scores mean a worse outcome. 1. Asymptomatic 2. Symptomatic, independent 3. Symptomatic, assistance needed 4. Hospitalized, no oxygen therapy 5. Hospitalized, mask or nasal prongs 6. Hospitalized, NIV o high flow 7. Intubation PaFi >150 8. Intubation PaFI <150 or vasopressors 9. Intubation PaFi <150 plus vasopressors or ECMO or dialysis 10. Dead
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    63
    60
    Units: subjects
        CAT 1
    42
    38
        CAT 2
    13
    14
        CAT 3
    0
    3
        CAT 4
    2
    0
        CAT 5
    1
    0
        CAT 6
    0
    0
        CAT 7
    0
    1
        CAT 8
    0
    0
        CAT 9
    0
    0
        CAT 10
    6
    4
    No statistical analyses for this end point

    Secondary: Secondary infections within 28d

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    End point title
    		 Secondary infections within 28d
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    63
    62
    Units: subjects
    7
    8
    No statistical analyses for this end point

    Secondary: Hyperglycaemia within 28d

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    End point title
    		 Hyperglycaemia within 28d
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    63
    62
    Units: subjects
    17
    5
    No statistical analyses for this end point

    Secondary: Psychotic states within 28d

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    End point title
    		 Psychotic states within 28d
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 250 mg methylprednisolone 6 mg dexamethasone
    Number of subjects analysed
    63
    62
    Units: subjects
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    90 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Treated
    Reporting group description
    		 patients on Methyprednisolone 250 mg intravenous per day x 3 days

    Reporting group title
    Active group
    Reporting group description
    		 control group, patients on RECOVERY scheme of treatment with dexamethasone 6 mg per day x 10 days

    Serious adverse events
    		 Treated Active group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 63 (34.92%)
    21 / 62 (33.87%)
         number of deaths (all causes)
    6
    4
         number of deaths resulting from adverse events
    6
    4
    Vascular disorders
    Thromboembolism
         subjects affected / exposed
    1 / 63 (1.59%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 63 (1.59%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    7 / 63 (11.11%)
    7 / 62 (11.29%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    COVID worsening
         subjects affected / exposed
    9 / 63 (14.29%)
    9 / 62 (14.52%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Pneumonia (no COVID)
         subjects affected / exposed
    6 / 63 (9.52%)
    4 / 62 (6.45%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    		 Treated Active group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 63 (39.68%)
    15 / 62 (24.19%)
    Cardiac disorders
    Arial fibrillation
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Heart failure
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Systemic blood hypertension
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    Thrombotic disorders
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 62 (3.23%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Respiratory function worsening
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    Tracheo-bronchitis
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Depressive anxiety disorder, confusion or depression
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 62 (1.61%)
         occurrences all number
    3
    1
    Endocrine disorders
    Hyperglycaemia
         subjects affected / exposed
    15 / 63 (23.81%)
    6 / 62 (9.68%)
         occurrences all number
    15
    6

    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
    15 Aug 2021
    The impact of vaccination programmes during early 2021 in Spain dramatically changed the characteristics of hospitalized patients with COVID-19. As older persons were prioritized for vaccination, an impressive decline occurred in the number of hospital admissions for patients aged over 70 years, resulting in a spectacular decrease in mortality rates. Taking this into consideration, our initial estimation for sample size calculation was outdated. In addition to the high percentage of people vaccinated in Spain32, in the summer of 2021 was the end of the fifth wave of COVID-19, with a very small number of patients hospitalized, so the clinical trial committee decided to conditionally stop the trial in August 2021.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The investigators considered that continuing the trial would be unlikely to change the results, so the trial was definitively stopped.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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