Covid-19 living Data

Corticosteroids vs Standard Care/Placebo (RCT)

Hospitalized patients

We requested data from three randomized trials evaluating corticosteroids that are yet to be published but were considered in the meta analysis" Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19 A Meta-analysis. We have extracted available data from this systematic review for the three unpublished studies. These have been included in our tables and forest plots.FOREST PLOTS -2022-12-06

Studies description

Trial NCT02735707
Publication REMAP-CAP - Angus DC, JAMA (2020) (published paper)
Dates: 2020-03-09 to 2020-06-17
Funding: Public/non profit (Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) consortium by the European Union, FP7-HEALTH-2013-INNOVATION-1, the Australian National Health and Medical Research Council, the New Zealand H)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Australia, Canada, France, Ireland, Netherlands, New Zealand, UK, USA Follow-up duration (days): 21
Inclusion criteria	Patients aged 18 years or older with presumed or confirmed SARS-CoV-2 infection who were admitted to an intensive care unit (ICU) for provision of respiratory or cardiovascular organ support were classified as severe and eligible for enrollment in the COVID-19 corticosteroid domain. An ICU could include an area of the hospital repurposed to function as an ICU for surge capacity management. Respiratory organ support was defined as invasive or noninvasive mechanical ventilation or high-flow nasal cannula if the flow rate was 30 L/minor greater and fraction of inspired oxygen of 0.4 or greater. Cardiovascular organ support was defined as the intravenous infusion of any vasopressor or inotrope.
Exclusion criteria	Report: Presumption that death is imminent with lack of commitment to full support and participation in the trial in the prior 90 days. Additional exclusion criteria for the corticosteroid domain included known hypersensitivity to hydrocortisone, systemic corticosteroid use, and more than 36 hours elapsed since ICU admission. Protocol (additional criteria): Patient has been randomized in a trial evaluating corticosteroids, where the protocol of that trial requires ongoing administration of study drug The treating clinician believes that participation in the domain would not be in the best interests of the patient
Interventions
	Treatment Fixed-dose hydrocortisone 50 mg IV infusion every 6 hours for 7 days
	Control Standard care
Participants
	Randomized participants : Fixed-dose hydrocortisone=143 Standard care=108
	Characteristics of participants N= 251 Mean age : NR 170 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=98 Critical: n=140
Primary outcome
	In the register All-cause mortality [ Time Frame: Day 90 ] Days alive and not receiving organ support in ICU [ Time Frame: Day 21 ]
	In the report Respiratory and cardiovascular organ support-free days up to day 21, an ordinal end point with death within the hospital as the worst outcome (labeled -1), then the length of time free of both respiratory and cardiovascular organ support, such that the best outcome would be 21 organ support–free days.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to all available versions of the published article, the study registry, supplementary documents and protocol were used in data extraction and risk of bias assessment. The study was terminated early. As a result, the target sample size specified in the registry was not achieved. Quote: "Following a press release from the RECOVERY trial on June 16, 2020, and in response to discussions held across the participating sites, the blinded international trial steering committee decided on June 17, 2020, to stop enrollment of patients with COVID-19 in the corticosteroid domain due to a loss of equipoise." There is no change from the trial registration in the intervention and control treatments. Outcome time points differ between the registry and the report but this could be due to the early termination. 'All cause mortality' is presented as the primary outcome in the registry and as secondary in the report.

Trial EudraCT202000193437
Publication GLUCOCOVID - Corral-Gudino L, medRxiv (2020) (preprint)
Dates: 2020-04-01 to 2020-05-31
Funding: No specific funding (The authors received no specific funding for this work)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Spain Follow-up duration (days): 28
Inclusion criteria	Eligible patients were hospitalized subjects over 18 years of age, with a laboratory confirmed diagnosis of SARS-CoV2 infection. Additional inclusion criteria were all the following: 1) Symptom duration of at least 7 days 2) Radiological evidence of lung disease in chest X-ray or CT-scan 3) Moderate-to-severe disease with abnormal gas exchange: PaFi (PaO2/FiO2) < 300, or SAFI (SAO2/FiO2) < 400, or at least 2 criteria of the BRESCIA-COVID Respiratory Severity Scale (BCRSS). 4) Laboratory parameters suggesting a hyper-inflammatory state: serum C-Reactive Protein (CRP) >15 mg/dl, D-dimer > 800 mg/dl, ferritin > 1000 mg/dl or IL-6 levels > 20 pg/ml.
Exclusion criteria	Patients were excluded if they were intubated or mechanically ventilated, were hospitalized in the ICU, were treated with corticosteroids or immunosuppressive drugs at the time of enrollment, have chronic kidney disease on dialysis, were pregnant or refused to participate.
Interventions
	Treatment Methylprednisolone 40 mg IV infusion twice a day for 3 days, then 20 mg twice a day for 3 days.
	Control Standard care
Participants
	Randomized participants : Methylprednisolone=35 Standard care=29
	Characteristics of participants N= 64 Mean age : NR 39 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=64 Critical: n=0
Primary outcome
	In the register Combination of death, ICU stay or non-invasive ventilation (NIV).
	In the report Composite endpoint that included in-hospital all-cause mortality, escalation to ICU admission, or progression of respiratory insufficiency that required non-invasive ventilation (NIV)
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to all available versions of the pre-print article, the study registry, the CAF reply and mail request for data reply was used in data extraction and risk of bias assessment. This is a report on preliminary results from an interim analysis. There is no change from the trial registration in the intervention and control treatments. Primary outcome in the registry and report is the same.

Trial NCT02517489
Publication Dequin P-F, JAMA (2020) (published paper)
Dates: 2020-03-07 to 2020-06-01
Funding: Public/non profit (French Ministry of Health, Programme Hospitalier de Recherche Clinique (PHRC))
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / France Follow-up duration (days): 28
Inclusion criteria	Patients aged at least 18 years admitted to 1 of the 9 participating French ICUs for acute respiratory failure could be included if they had a biologically confirmed (reverse transcriptase-polymerase chain reaction) or suspected (suggestive chest computed tomography scan result in the absence of any other cause of pneumonia) COVID-19. The experimental treatment had to be administered within 24 hours of the onset of the first severity criterion (see below) or within 48 hours for patients referred from another hospital. One of 4 severity criteria had to be present: need for mechanical ventilation with a positive end-expiratory pressure (PEEP) of 5 cm H20 or more a ratio of Pao2 to fraction of inspired oxygen (Fio2) less than 300 on high-flow oxygen therapy with an Fio2 value of at least 50% for patients receiving oxygen through a reservoir mask, a Pao2:Fio2 ratio less than 300, estimated using prespecified charts or a Pulmonary Severity Index greater than 130. Patients receiving vasopressors to correct hypotension related to sedative drugs and mechanical ventilation at high PEEP levels could be included.
Exclusion criteria	Report: septic shock and do-not-intubate orders Protocol and Registry: •Patient treated by vasopressors for septic shock at the time of inclusion •Clinical history suggesting of aspiration of gastric content •Patient treated by invasive mechanical ventilation within 14 days before current hospital admission •Patient treated by antibiotics for a respiratory infection for more than seven days at the admission to the hospital (except if a pathogen resistant to this antibiotics is isolated) •History of cystic fibrosis •Post-obstructive pneumonia •Patients in which rapid PCR-test is positive for flu •Active tuberculosis or fungal infection •Active viral hepatitis or active infection with herpes viruses •Myelosuppression •Decision of withholding mechanical ventilation or endotracheal intubation •Hypersensitivity to corticosteroids •Patient needing anti-inflammatory corticosteroids or substitutive hydrocortisone for any reason •Patients under treatment by more than 15 mg/d of prednisone (or equivalent) for more than 30 days •Patient already enrolled in another drug trial with mortality as an end-point. If the patient is already participating in another therapeutic trial with a different endpoint, the investigator must verify that inclusion in CAPE COD can not prejudice it. •Pregnant or breastfeeding woman •Patient on judicial protection
Interventions
	Treatment Hydrocortisone 200 mg IV infusion once a day for 7 days, then 100 mg once a day for 4 days, followed by 50 mg once a day for 3 days.
	Control Placebo
Participants
	Randomized participants : Hydrocortisone=76 Placebo=73
	Characteristics of participants N= 149 Mean age : NR 104 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=28 Critical: n=121
Primary outcome
	In the register Day 28 all causes mortality [ Time Frame: at day 28 ] Day 21 failure [ Time Frame: at day 21 ]
	In the report Treatment failure on day 21
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to all available versions of the published article, the study registry, protocol and statistical analysis plan were used in data extraction and risk of bias assessment. The study was terminated early considering that it would be unethical to resume a corticosteroid vs placebo trial. As a result, the target sample size (290) was not achieved. Quote: "On June 30, 2020, the DSMB recommended suspension of inclusions pending publication of the results of the RECOVERY trial and possible changes in treatment recommendations. The sponsor decided to discontinue the study on July 3, 2020, considering that it would be unethical to resume a corticosteroid vs placebo trial". There is no change from the trial registration in the intervention and control treatments nor the primary outcome. Some secondary outcomes in the registry are not present in the report (All-causes mortality at day 90, SF-36 Health Survey at day 90, Weight-gain at baseline and day 7, Biomarkers: procalcitonin at baseline, day 3 and day 7,C-reactive protein at baseline, day 3 and day 7 ,plasmatic concentration of pro-inflammatory cytokines (IL-6, IL-20, IL-22, IL-22BP, HBD2, TNF) at baseline, day 3 and day 7) This trial was embedded in the ongoing Community- Acquired Pneumonia:Evaluation of Corticosteroids(CAPE-COD) trial.

Trial NCT04244591
Publication Steroids-SARI - Du, Unpublished (2020) ( )

Funding: Public/non profit (Peking Union Medical College Hospital, Zhongda Hospital, Zhongnan Hospital, Renmin Hospital of Wuhan University)
Conflict of interest: *

Trial IRCT20200404046947N1
Publication Edalatifard M, Eur Respir J (2020) (published paper)
Dates: 2020-04-20 to 2020-06-20
Funding: Public/non profit (Deputy of Research, Tehran University of Medical Sciences)
Conflict of interest: No

Methods
	RCT Blinding: single blinding
	Location : Multicenter / Iran Follow-up duration (days): 60
Inclusion criteria	Aged 18 years or older Confirmed COVID-19 (RT-PCR) Abnormal computed tomography (CT) scan with blood oxygen saturation <90%, elevated C-reactive protein (CRP >10), and interleukin (IL)-6 (>6) at the early pulmonary phase of disease before connecting to the ventilator and intubation,agreed to give informed consent.
Exclusion criteria	Patients intolerant or allergic to any therapeutic agents used in this research Pregnant or lactating women blood oxygen saturation <75%, positive pro-calcitonin (PCT) and troponin test, Acute Respiratory Distress Syndrome (ARDS), uncontrolled hypertension (HTN), uncontrolled diabetes mellitus (DM), gastrointestinal problems or gastrointestinal bleeding (GIB) history, heart failure (HF), active malignancies and received any immune-suppressor agents.
Interventions
	Treatment IVMP Pulse 250 mg IV injection once a day for 3 days
	Control Standard care
Participants
	Randomized participants : IVMP Pulse=34 Standard care=34
	Characteristics of participants N= 68 Mean age : NR 39 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=68 Critical: n=0
Primary outcome
	In the register Radiographic features Findings
	In the report time of clinical improvement and discharge from the hospital or death whichever came first
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the study registry was used in data extraction and risk of bias assessment. The trial registration was updated between completion and submission of report manuscript for publication to change from double-blinded to single-blinded, increase the sample size from 40 to 68, and alter the timing of outcome measurement. The primary outcome and some other outcomes in the published report differ from those in the registration. There is no change from the trial registration in the intervention and control treatments. The primary outcome and some other outcomes in the published report differ from those in the registration.

Trial IRCT20200406046963N1
Publication Farahani R, Research Square (2020) (preprint)
Dates: 2020-04-01 to 2020-05-30
Funding: Public/non profit (AJA University of Medical Science)
Conflict of interest: No

Trial NCT04381936
Publication RECOVERY (Dex) - Horby P, N Engl J Med (2021) (published paper)
Dates: 2020-03-19 to 2020-06-08
Funding: Mixed (University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR); NIHR Oxford Biomedical Research Centre; Wellcome; Bill and Melinda Gates Foundation; Department for International Development; Health Data Research UK)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / UK Follow-up duration (days): 28
Inclusion criteria	Hospitalized patients suspected or laboratory confirmed SARS-CoV-2 infection no medical history that might, in the opinion of the attending clinician, put the patient at significant risk no age limit Pregnant or breast-feeding women were eligible.
Exclusion criteria	One or more of the active drug treatments is not available at the hospital or is believed, by the attending clinician, to be contraindicated (or definitely indicated) for the specific patient
Interventions
	Treatment Dexamethasone 6 mg orally or IV infusion once daily for up to 10 days (or until hospital discharge if sooner)
	Control Standard care
Participants
	Randomized participants : Dexamethasone=2104 Standard care=4321
	Characteristics of participants N= 6425 Mean age : NR 4087 males Severity : Mild: n=1535 / Moderate: n=* / Severe: n=* Critical: n=1007
Primary outcome
	In the register All-cause mortality [ Time Frame: Within 28 days after randomisation ]
	In the report 28-day mortality
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published/pre-print report, the study registry, protocol, and statistical analysis plan were used in data extraction and risk of bias assessment. The RECOVERY trial is an investigator-initiated, individually randomized, controlled, open-label, adaptive platform trial to evaluate the effects of potential treatments in patients hospitalized with COVID-19. The trial was conducted at 176 National Health Service (NHS) hospital organizations in the United Kingdom. There is no change from the trial registration in the intervention and control treatments. All outcomes from the registry are reported in the paper. Pre-specified analyses of the primary outcome were performed in five subgroups defined by characteristics at randomization: age, sex, level of respiratory support, days since symptom onset, and predicted 28-day mortality risk. An adjustment for age, a key prognostic factor, that was not specified in the first version of the statistical analysis plan, but was added once the imbalance in age became apparent was performed and reported in the paper. On 19th of May 2021, this study was updated based on the published report with updated results.

Trial IRCT20151227025726N17
Publication Jamaati H, Eur J Pharmacol (2021) (published paper)

Funding: Public/non profit (Shahid Beheshti University of Medical Sciences)
Conflict of interest: No

Trial NCT04438980 ; EudraCT 2020-001827-15
Publication CORTIVID - Les I, Front Med (2022) (published paper)
Dates: 2020-05-08 to 2021-03-13
Funding: Public/non profit (ISCIII - Instituto de Salud Carlos III (Carlos III Health Institute) )
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Spain Follow-up duration (days): 28
Inclusion criteria	≥18 years old had been admitted with SARS-CoV-2 pneumonia confirmed by a positive reverse-transcription polymerase chain reaction (RT-PCR) of nasopharyngeal swab, defined as a cycle threshold (Ct) ≤ 35 presented with symptoms compatible with COVID-19 for at least 7 days and had at least one of the following - C-reactive protein (CRP) >60 mg/L, interleukin (IL)-6 > 40 pg/ml, or ferritin >1,000 μg/L.
Exclusion criteria	Allergy to or contraindication for corticosteroids an indication other than COVID-19 for treatment with corticosteroids or immunosuppressants respiratory failure, defined as a peripheral oxygen saturation (SpO2) below 90% in ambient air or a ratio between the arterial partial pressure of oxygen (PaO2) and the fraction of inspired oxygen (PaO2/FiO2) below 300 as a result of the use of dexamethasone as the standard of care in June 2020, patients with a SpO2 < 94% in ambient air were excluded from the study as of July 2020 decompensated diabetes mellitus uncontrolled hypertension active cancer conservative or palliative management a suspected or confirmed active infection other than SARS-CoV-2 pregnancy or breastfeeding or participation in another clinical trial.
Interventions
	Treatment IVMP Pulse 120 mg intravenously once a day for 3 days
	Control Placebo
Participants
	Randomized participants : IVMP Pulse=34 Placebo=38
	Characteristics of participants N= 72 Mean age : NR 49 males Severity : Mild: n=0 / Moderate: n=71 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Proportion of patients developing treatment failure [ Time Frame: At 14 days after randomization ] Death; Need for admission in an intensive care unit (ICU); Need for mechanical ventilation; Decrease in SpO2 <90% (in ambient air) or PaO2 <60 mmHg (in ambient air) or PaO2FiO2 <300 mmHg, associated with radiological impairment
	In the report Treatment failure, defined as death, ICU admission, initiation of MV, or clinical worsening up to 14 days post-randomization. Clinical worsening was considered when at least one of the following two conditions was met: (1) SpO2 in ambient air below 90%, PaO2 in ambient air below 60 mmHg, or PaO2/FiO2 ratio below 300 mmHg; or (2) at least 15% decrease in the PaO2 from baseline, together with an increase in the levels of any inflammatory marker (CRP, IL-6, or ferritin) or radiological progression.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the trial registries, protocol, statistical analysis plan and supplementary appendices were used in data extraction and assessment of risk of bias. The primary and secondary outcomes in the article reflect those in the registries. The trial (n = 72) achieved its target sample size (n = 72). This study was updated on August 4th, 2022 with data extracted after contact with authors.

Trial NCT04348305
Publication COVID STEROID - Munch MW, Acta Anaesthesiol Sc (2021) (published paper)
Dates: 2020-04-17 to 2020-06-16
Funding: Mixed (Novo Nordisk Foundation, Rigshospitalet's Research Council, and Pfizer.)
Conflict of interest: No

Methods
	RCT Blinding: quadruple blinding
	Location : Multicenter / Denmark Follow-up duration (days): 90
Inclusion criteria	Age ≥18 years confirmed SARS-CoV-2 (COVID-19) requiring hospitalisation Use of one of the following: invasive mechanical ventilation or non-invasive ventilation or continuous use of continuous positive airway pressure (CPAP) for hypoxia or oygen supplementation with an oxygen flow of at least 10L.min independent of delivery system
Exclusion criteria	Use of systemic corticosteroids Invasive mechanical ventilation >48 hours prior to screening Invasive fungal infection Fertile woman (<60 years of age) with positive urine human gonadotropin (hCG) or plasma‐hCG Known hypersensitivity to hydrocortisone A patient for whom the clinical team has decided not to use invasive mechanical ventilation Previously randomised into the COVID STEROID trial Informed consent not obtainable.
Interventions
	Treatment Hydrocortisone 200 mg per day either as continuous infusion or as bolus injections every 6 hours (50 mg per bolus) for 7 days or until hospital discharge (whichever came first).
	Control Placebo
Participants
	Randomized participants : Hydrocortisone=16 Placebo=14
	Characteristics of participants N= 30 Mean age : NR 24 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=19 Critical: n=11
Primary outcome
	In the register Days alive without life support at day 28 [Time Frame: Day 28 after randomisation]
	In the report 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) at day 28
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	In addition to the published article, the original and published protocols, statistical analysis plan, registries (EudraCT 2020-03-30; NCT submitted 2020-04-14) and supplementary appendices were used in data extraction and assessment of risk of bias. The primary outcome indicated in registry reflects the primary outcome reported in the paper. Long-term outcomes in the registry (all-cause mortality and health-related quality of life at 1 year) are not reported in this article. The study was terminated after 30 patients were enrolled due to low recruitment. The trial was terminated due to information from the RECOVERY trial and from a WHO-initiated meta-analysis of ongoing or recently completed trials demonstrating benefit from systemic corticosteroids on 28-day mortality in critically ill patients with COVID-19. The planned sensitivity analyses could not be completed because of low sample size. The study did not achieve the target sample size.

Trial NCT03852537
Publication SMART Trial - Odeyemi YE, Crit Care (2022) (published paper)
Dates: 2020-03-01 to 2020-11-30
Funding: Public/non profit (The American Heart Association COVID-19 Rapid Response Grant. The Mayo Clinic Critical Care Independent Multidisciplinary Program (IMP) Research Grant (Institutional Departmental grant). National Center for Advancing Translational Science (NCATS). National Heart, Lung, and Blood Institute)
Conflict of interest: No

Methods
	RCT Blinding: single blinding
	Location : Single center / USA Follow-up duration (days): 90
Inclusion criteria	Patients admitted to hospital with COVID-19 pneumonia (high suspicion or confirmed by positive SARS CoV-2 testing) Acute respiratory failure SpO2/FiO2 < 315 (SpO2<90% on room air or <97% on 2L NC).
Exclusion criteria	Contraindications or unwilling to use steroids by patient or provider Refractory septic shock defined as a requirement of norepinephrine dose or equivalent above >0.1 microgram/kilogram/minute or 2 or more vasopressors Pre-admission chronic use of steroids or other immunosuppressive medications Adrenal insufficiency Comfort care Leukopenia <1000/mm or neutropenia <500/mm (except if attributable to pneumonia) and HIV positive with a CD4 count <100 Recent or past history of bone marrow or solid organ transplantation Suspected flare of Interstitial lung disease (infectious and non-infectious) Positive influenza testing or high suspicion for influenza
Interventions
	Treatment Methylprednisolone 0.5 to 1.5 mg/kg methylprednisolone (or dose equivalent of oral prednisone) adjusted to daily CRP level.
	Control Standard care
Participants
	Randomized participants : Methylprednisolone=19 Standard care=22
	Characteristics of participants N= 41 Mean age : NR 24 males Severity : Mild: n=4 / Moderate: n=25 / Severe: n=14 Critical: n=2
Primary outcome
	In the register Timely Initiation of Corticosteroids and Implementation of Biomarker-titrated Corticosteroid Dosing [ Time Frame: Within 30 days of enrollment in study. ] Number of eligible subjects to adhered to the timely initiation and daily corticosteroid treatment according to ESICM/Society of Critical Care Medicine SCCM clinical practice guideline (control group) or biomarker concordance (intervention group)
	In the report feasibility of the trial protocol
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to the published article, the registry, protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. This pilot trial was originally planned and registered in early 2019 to investigate biomarker-guided corticosteroid use in pneumonia and acute hypoxemic respiratory failure. A separate COVID-19 arm was added in 2020. There was a change to standard care due to the results of the RECOVERY trial. The primary feasibility outcome in the article reflects that in the registry and all planned outcomes are reported in the registry. Results were also posted on the trial registry but data from direct contact with authors was given priority. This study was updated on April 28th, 2022 with data acquired after contact with authors.

Trial NCT04343729
Publication Prado Jeronimo CM, Clin Infect Dis (2020) (published paper)
Dates: 2020-04-08 to 2020-06-16
Funding: Public/non profit (Superintendencia da Zona Franca de Manaus, Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Departamento de Ciencia e Tecnologia/Ministerio da Saude, Ministerio da Ciencia, Tecnologia e Inovacoes, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Fundacao de Amparo a Pesquisa do Estado do Amazonas)
Conflict of interest: No

Trial NCT04673162 ; EudraCT 2020-004323-16
Publication Salvarani C, Eur Respir J (2022) (published paper)
Dates: 2020-12-21 to 2021-03-10
Funding: No specific funding (This research received no external funding. The coordinator centre and all participating centres are using local resources to conduct the trial.)
Conflict of interest: No

Methods
	RCT Blinding: triple blinding
	Location : Multicenter / Italy Follow-up duration (days): 30
Inclusion criteria	Patients hospitalized for recent-onset COVID-19 pneumonia documented by radiological imaging confirmed by polymerase chain reaction method with nasopharyngeal swab more than five days since initial symptoms of infection requiring supplemental oxygen in any delivery mode, except invasive mechanical ventilation PaO2/FiO2 between 100 and 300 a C-reactive protein (CRP) greater than 5 mg/dL.
Exclusion criteria	Required invasive mechanical ventilation shock or concomitant organ failure requiring an Intensive Care Unit (ICU) admittance pregnancy or breastfeeding severe cardiac or renal failure diabetes not in good metabolic control based on physician’s clinical judgment other clinical conditions which contraindicate methylprednisolone and which cannot be treated or resolved based on physician’s clinical judgment therapy with steroid high dose pulses in the week preceding the enrolment in the study enrolment in another clinical trial.
Interventions
	Treatment Methylprednisolone 1 g/day intravenously in 100 ml once a day for 3 days
	Control Placebo
Participants
	Randomized participants : Methylprednisolone=152 Placebo=152
	Characteristics of participants N= 304 Mean age : NR 217 males Severity : Mild: n=0 / Moderate: n=205 / Severe: n=96 Critical: n=0
Primary outcome
	In the register Length of hospitalization [Time Frame: 30 days since randomisation] the interval between randomization and discharge from the hospital without the need for supplemental oxygen
	In the report The duration of the patient hospitalisation, calculated as the interval of time between the randomisation and the hospital discharge without the need of supplementary oxygen during the first 30 days following randomisation.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	In addition to the published article, the prospective registries and supplementary appendices were used in data extraction and assessment of risk of bias. The protocol and statistical analysis plan referred to as supplementary appendices in the early view article were not accessible at time of extraction. The primary outcome in the article reflects that in the registry. The trial (n = 304) achieved its target sample size (n = 260).

Trial NCT04273321
Publication Tang X, Respiration (2021) (published paper)
Dates: 2020-02-19 to 2020-03-31
Funding: Public/non profit (Beijing Municipal Admin of Hospitals’ Mission Plan; Excellence Prog of Beijing Clin Key Specialty; Novel Coronavirus Pneumonia Key Tech R&D Funding of Beijing Municipal Admin of Hospitals)
Conflict of interest: No

Methods
	RCT Blinding: single blinding
	Location : Multicenter / China Follow-up duration (days): 30
Inclusion criteria	Patients who were laboratory confirmed of SARS-CoV-2 infection and had pneumonia confirmed by chest computed tomography Aged 18 years or older Admitted to the general wards for less than 72 h Able to sign informed consent.
Exclusion criteria	Severe immunosuppression (human immunodeficiency virus infection and long-term use of immunosuppressive agents) Pregnant or breastfeeding women Corticosteroid needed for other diseases Refractory hypertension, Epilepsy or delirium, glaucoma, active gastrointestinal bleeding within 3 months Refractory hypokalemia, secondary bacterial or fungal infection Unwilling or unable to participate or complete the study Participation in other studies.
Interventions
	Treatment Methylprednisolone 1 mg/kg/day in 100 mL 0.9% normal saline IV for 7 days
	Control Placebo
Participants
	Randomized participants : Methylprednisolone=43 Placebo=43
	Characteristics of participants N= 86 Mean age : NR 41 males Severity : Mild: n=0 / Moderate: n=45 / Severe: n=41 Critical: n=0
Primary outcome
	In the register Incidence of treatment failure in 14 days [ Time Frame: 14 days ]. The clinical symptoms and signs continue to deteriorate, or new pulmonary or extrapulmonary lesions appear, or the chest imaging indicates the progress, and the patient is transferred to ICU or intubation and invasive ventilation or died.
	In the report Incidence of clinical deterioration 14 days after randomization.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the prospective trial registry and supplementary materials were used in data extraction and assessment of risk of bias. There were no substantive changes between the trial registry and the published article in population, procedures and interventions. In addition to the outcomes included in the trial registry, the article reports the effect of methylprednisolone treatment of immune cell profile determined by mass cytometry. The study was terminated early and did not achieve its pre-stated target sample size due to a rapid decrease in potentially eligible patients.

Trial NCT04327401
Publication Tomazini BM, JAMA (2020) (published paper)
Dates: 2020-04-17 to 2020-06-23
Funding: Mixed (Coalition COVID-19 Brazil; Laboratorios Farmaceuticos)
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Brazil Follow-up duration (days): 28
Inclusion criteria	1) Age >/=18 years old 2) Probable or confirmed infection by SARS-CoV2 3) Intubated and mechanically ventilated 4) Moderate or severe ARDS according to Berlin criteria3 (Partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2:FiO2) ratio of 200 or less, with positive end expiratory pressure (PEEP) of at least 5 cm of water, bilateral opacities and respiratory failure not fully explained by heart failure or fluid overload) 5) Within 48 hours of meeting criteria for moderate or severe ARDS
Exclusion criteria	1) Pregnancy or active lactation 2) Known history of dexamethasone allergy 3) Corticosteroids use in non hospitalized patients in the past 15 days 4) Indication for corticosteroids use for other clinical conditions (e.g refractory septic shock) 5) Patients who used corticosteroids during hospital stay for more than one day 6) Use of immunosuppressive drugs 7) Cytotoxic chemotherapy in the past 21 days 8) Neutropenia due to hematological or solid malignancies with bone marrow invasion 9) Patients expected to die in the next 24 hours 10) Consent refusal for participation
Interventions
	Treatment Dexamethasone 20 mg IV once a day for 5 days, then 10 mg IV once a day for 5 days
	Control Standard care
Participants
	Randomized participants : Dexamethasone=151 Standard care=148
	Characteristics of participants N= 299 Mean age : NR 187 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=0 Critical: n=299
Primary outcome
	In the register Ventilator-free days [ Time Frame: 28 days after randomization ]
	In the report Ventilator-free days during the first 28 days, defined as the number of days alive and free from mechanical ventilation for at least 48 consecutive hours.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to all available versions of the published article, the study registry, statistical analysis plan and protocol were used in data extraction and risk of bias assessment. The study was terminated early. As a result, the target sample size (350) was not achieved. Quote: "On June 25, 2020, the DSMC discussed the implications of the results of the dexamethasone group in the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial, stating that given the study results,15 it was no longer ethical to continue the trial, which led to the recommendation to stop the trial. This recommendation was accepted by the CoDEX Steering Committee on June 25, 2020" There is no change from the trial registration in the intervention and control treatments, as well as, primary and secondary outcomes.

Trial NCT04325061
Publication DEXA-COVID19 - Villar J, Unpublished (2020) ( )

Funding: Public/non profit (Instituto de Salud Carlos III, Madrid, Spain(CB06/06/1088, PI19/00141); Asociación Científica Pulmón y VentilaciónMecánica, Las Palmas de Gran Canaria, Spain; and the Canadian Institute for Health Research, Ottawa, Canad)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Spain Follow-up duration (days): 60
Inclusion criteria	Age 18 years or older Positive reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay for COVID-19 in a respiratory tract sample Intubated and mechanically ventilated Acute onset of ARDS, as defined by Berlin criteria as moderate-to-severe ARDS,3 which includes: (i) having pneumonia or worsening respiratory symptoms, (ii) bilateral pulmonary infiltrates on chest imaging (x-ray or CT scan), (iii) absence of left atrial hypertension, pulmonary capillary wedge pressure <18 mmHg, or no clinical signs of left heart failure, and (iv) hypoxemia, as defined by a PaO2/FiO2 ratio of ≤200 mmHg on positive end-expiratory pressure (PEEP) of ≥5 cmH2O, regardless of FiO2.
Exclusion criteria	Routine treatment with corticosteroids during the previous week irrespective of dose Corticosteroid use within the previous 24 h of more than 20 mg of dexamethasone or equivalent Patients with a known contraindication to corticosteroids Decision by a physician that involvement in the trial is not in the patient's best interest Pregnancy and breast-feeding Participation in another therapeutic trial.
Interventions
	Treatment Dexamethasone 20mg IV once a day for 5 days and then 10mg IV once a day for 5 days
	Control Standard care
Participants
	Randomized participants : Dexamethasone=7 Standard care=12
	Characteristics of participants N= 19 Mean age : NR 13 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=0 Critical: n=19
Primary outcome
	In the register 60-day mortality [ Time Frame: 60 days ]
	In the report NR
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	The study is not published yet. Data presented was extracted from study registry, protocol and Sterne, Jonathan AC, et al. "Association between Administration of Systemic Corticosteroids and Mortality among critically ill patients with COVID-19: a meta-analysis." Jama (2020). The authors have been contacted in order to obtain the results.

Methods
	RCT Blinding: double blinding
	Location : Single center / Iran Follow-up duration (days): *
Inclusion criteria	Patients 18 years of age or older with moderate to severe Covid-19 infection who admitted to ICU with PaO2/FiO2 less than 300 and progressive disease not responding to recommended treatment with the prediction of need for intubation within next 24 hours
Exclusion criteria	Patients with uncontrolled diabetes mellitus, Active GI bleeding, history of corticosteroid hypersensitivity, severe electrolyte imbalances, Procalcitonin more than 0.5, active bacterial, viral (HIV, Hepatitis), and fungal infection
Interventions
	Treatment IVMP Pulse+Pred Methylprednisolone: 1000 mg IV injection once a day for three days. Prednisolone: 1 mg/kg orally with tapering of dose within ten days
	Control Standard care
Participants
	Randomized participants : Standard care=15 IVMP Pulse+Pred=14
	Characteristics of participants N= 29 Mean age : NR 19 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=29 Critical: n=0
Primary outcome
	In the register Mortality rate, blood O2 saturation, and need for further oxygen therapy
	In the report Mortality rate, blood O2 saturation, and need for further oxygen therapy
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	*
General comment	This study is pending author reply. Data per arm for the outcomes were not reported. In addition to the available version of the pre-print, the study registry was used in data extraction and risk of bias assessment. The study did not achieve the target sample size specified in the trial registry. There is no change from the trial registration in the intervention and control treatments. The registry primary outcomes reflect the reported primary outcomes, however some secondary outcomes from the registry are not reported in the paper (e.g., ICU length of stay). Adverse events are not reported. Other secondary outcomes (e.g., CPK, LDH) are reported in the paper, but not pre-specified in the trial registry.

Methods
	RCT Blinding: double blinding
	Location : Single center / Brazil Follow-up duration (days): 28
Inclusion criteria	Hospitalized patients were included if they had clinical AND/OR radiological suspicion of COVID-19 (history of fever AND any respiratory symptom, e.g., cough or dyspnea AND/OR ground glass opacity OR pulmonary consolidation on CT scan), aged 18 years or older at the time of inclusion, with SpO2 < 94% at room air OR in use of supplementary oxygen OR under IMV. Children under 18 years of age were not included due to the known lower morbidity/mortality from COVID-19.
Exclusion criteria	Patients were excluded if they had a history of hypersensitivity to MP, HIV/AIDS, chronic use of corticosteroids or immunosuppressive agents, pregnant or breastfeeding, decompensated cirrhosis or chronic renal failure.
Interventions
	Treatment Methylprednisolone 0.5 mg/kg IV twice daily for 5 days
	Control Placebo
Participants
	Randomized participants : Placebo=207 Methylprednisolone=209
	Characteristics of participants N= 416 Mean age : NR 271 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register Mortality rate at day 28
	In the report 28-day mortality
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to the accepted manuscript, the study registry, protocol and statistical analysis plan was used in data extraction and risk of bias assessment. The study achieved the target sample size reported in the registry. There is no change from the trial registration in the intervention and control treatments. There is no change from the trial registration in the primary outcomes. Some secondary outcomes in the report are not present in the registry. The trial reported mITT analyses in the report and ITT analyses in a supplementary file but not for all outcomes such as time to death.