Corticosteroids

Dexamethasone

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Tomazini et al.

2020

Type of study:

Multicenter, randomized, open-label, clinical trial

Setting:

41 intensive care units (ICUs)

Country:

Brazil

Source of funding:

This trial was funded and supported by the Coalition COVID-19 Brazil. The Laboratórios Farmacêuticos provided the study drug, distribution logistics, and insurance for the study patients.

Sample characteristics:

Patients with severe disease: intubated and mechanically ventilated.

Inclusion criteria:

• Age ≥18 yrs;
• Probable or confirmed infection by SARS-CoV2;
• Intubated and mechanically ventilated;
• Moderate or severe ARDS according to Berlin criteria;
• Within 48 hours of meeting criteria for moderate or severe ARDS.

Exclusion criteria:

• Pregnancy or active lactation;
• Known history of dexamethasone allergy;
• Corticosteroids use in non hospitalized patients in the past 15 days;
• Indication for corticosteroids use for other clinical conditions;
•  Patients who used corticosteroids during hospital stay for more than one day;
• Use of immunosuppressive drugs;
• Cytotoxic chemotherapy in the past 21 days;
• Neutropenia due to hematological or solid malignancies with bone marrow invasion;
• Patients expected to die in the next 24 hours;
• Consent refusal for participation.

N total at baseline:

N = 299

Intervention: 151

Control: 148

Important characteristics:

Age, mean (SD):

I: 60.1 yrs (15.8)

C: 62.7 yrs (13.1)

Sex, n/N (%) male:

I: 90/151 male (59.6%)

C: 97/148 male (65.6%)

Baseline characteristics were well balanced between groups

dexamethasone 20 mg intravenously once daily for 5 days, followed by 10 mg intravenously once daily for additional 5 days or until ICU discharge, whichever occurred first, plus standard care.

All clinical interventions,

such as use of antibiotics, ventilatory strategy, laboratory testing, and hemodynamic management were left at the discretion of the ICU team for both groups.

Standard care only

28 days after randomization or until hospital discharge, whichever occurred first.

Clinical outcomes

All-cause mortality, n/N (%) at 28 days

I: 85/151 (56.3%)

C: 91/148 (61.5%)

Adj. HR= 0.97 (95% CI= 0.72 to 1.31)

P=0.85

Unadj. HR= 0.86 (95% CI= 0.64 to 1.15)

P=0.31

Days alive and ventilator free at 28 days, mean (95% CI)

I: 6.6 (95% CI 5.0 to 8.2)

C: 4.0 (95% CI= 2.9 to 5.4)

Adj. MD= 2.26 (95% CI = 0.2 to 4.38)

P=0.04

Unadj. MD= 2.55 (95% CI= 0.46 to 4.6)

P=0.02

ICU free days, mean (95% CI)

I: 2.1 (95% CI= 1.0 to 4.5)

C: 2.0 (95% CI= 0.8 to 4.2)

Adj. MD= 0.28 (95% CI= -0.49 to 1.02)

P=0.50

Unadj. MD= 0.14 (95% CI= -0.92 to 1.27)

P=0.78

Mechanical ventilation days, mean (95% CI)

I: 12.5 (95% CI= 11.2 to 13.8)

C: 13.9 (95% CI= 12.7 to 15.1)

Adj. MD= -1.54 (95% CI= -3.24 to 0.12)

P=0.11

Unadj. MD= -1.46 (95% CI = -3.10 to 0.57)

P=0.18

Serious adverse events, n/N (%)

I: 5/151 (3.3%)

C: 9/148 (6.1%)

AD= 2.8 (95% CI= -2.7 to 8.2)

*AD = absolute difference

Clinical status of patient (day 15)

I: 5 (3 to 6)

C: 5 (5 to 6)

Adj. OR=0.66 (95% CI = 0.43 to 1.03) P = 0.07

Unadj. OR=0.62 (95% CI = 0.41 to 0.94) P=0.03

Also available

• Sequential Organ Failure Assessment (SOFA)
• Other adverse events
• Subgroup analysis based on age

Virological outcomes

not reported

Definitions:

clinical status of patients: using a 6-point ordinal scale adapted from the World Health Organization

R&D Blueprint expert group.

Remarks:

• Second, 35%of the patients in the control group received corticosteroids during the study period
• the study was interrupted before the original sample size was obtained

Conflict of interests

• Multiple authors reported support from pharmaceutical or other companies.
• Regarding funding of study: support from pharmaceutical company in terms of providing of drugs, logistics, insurance.

Authors conclusion:

In patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care, compared with standard care alone, resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.

Jamaati, 2021

Type of study:

RCT, clinical trial

Setting:

Conducted in

March 2020 at Dr. Masih Daneshvari Hospital: primary

referral center for patients with COVID-19.

Country:

Iran

Source of funding:

None

Hospitalized patients with mild

to moderate acute respiratory distress syndrome (ARDS) due to COVID-19

Inclusion criteria:

• Age > 18y;
• Confirmed SARS-CoV-2 infection;
• PaO2/FiO2 between 100 and 300 mmHg;
• Bilateral lung infiltration;
• Written informed consent by the patient.

Exclusion criteria:

• Chronic kidney disease;
• Chronic liver disease;
• Hyperglycemia;
• Pregnant or breastfeeding.

N total at baseline:

N = 50

Intervention: 25

Control: 25

Important characteristics:

Age, median (IQR):

I: 62 y (52-71)

C: 62 y (54-68)

Sex, n/N (%) male:

I: 18/25 (72%)

C: 18/25 (72%)

Disease severity:

Defined by symptoms, n (%)/N

Fever

I: 16 (64%) / 25

C:18 (72%) / 25

Cough

I: 15 (60%) / 25

C: 14 (56%) / 25

Dyspnea

I: 7 (28%) / 25

C: 20 (80%) / 25

Myalgia

I: 1 (4%) / 25

C: 8 (32%) / 25

Nausea or vomiting

I: 1 (4%) / 25

C: 1 (4%) / 25

Groups were comparable at baseline, with the exception of the number of patients with pulmonary diseases as part of their medical history. This number was higher in the control group (I: 1, C: 9).

Intravenous dexamethasone at a dose of 20 mg/day from day 1–5 and then at 10 mg/day from day 6–10 + standard care

Standard care only

Length of follow up:

28 days

Loss to follow-up:

I: 0/25 (%)

C: 0/25 (%)

Clinical outcomes

Mortality (n (%)/N) within 28 days

I: 16/25 (64%)

C: 15/25 (60%)

RR: 1.07 [95% CI 0.69 to 1.65]

Discharged patients within 28 days

I: 9/25 (37%)

C: 10/25 (40%)

RR: 0.90 [95% CI 0.44 to 1.83]

Duration of hospitalization (days), median (IQR)

Overall

I: 11 (6–16)

C: 6 (4–9)

Survivors (sub-group)

I: 16 (9-21), n=9

C: 8.5 (5-13), n=10

Non-survivors (sub-group)

I: 9.5 (5.5-13), n=16

C: 6 (3-7), n=15

Duration of ICU stay (days),

median (IQR)

Overall

I: 7 (4–11)

C: 3 (2–5)

Survivors (sub-group)

I: 7 (4-12), n=9

C: 4.5 (3-5), n=10

Non-survivors (sub-group)

I: 7 (4.5-10), n=16

C: 3 (2-3), n=15

Symptom resolution

Not reported

Need for non-invasive ventilation, n(%)/N

Overall

I: 23 (92%) / 25

C: 24 (96%) / 25

Survivors (sub-group)

I: 9 (100%), n=9

C: 10 (100%), n=10

Non-survivors (sub-group)

I: 14 (88%), n=16

C: 14 (93%), n=15

Among the patients who required non-invasive ventilation, the following numbers of patients required invasive mechanical ventilation:

Need for invasive ventilation

Overall

I: 13 (52%) / 25

C: 11 (44%) / 25

Survivors (sub-group)

I: 2 (22%), n=9

C: 1 (10%), n=10

Non-survivors (sub-group)

I: 11 (69%), n=16

C: 10 (67%), n=15

SOFA-score, mean (SD)

Overall

I: 4.68 (1.38)

C: 4.56 (1.36)

Survivors (sub-group), median (IQR)

I: 4 (4-5) n=9

C: 4 (4-5), n=10

Non-survivors (sub-group), median (IQR)

I: 5 (4-6), n=16

C: 4 (4-6), n=15

Improvements in lung CT scan images

I: 40% of patients

C: 12% of patients

Safety

Adverse events

Not reported

Virological outcomes

Viral clearance

Not reported

Definitions:

Remarks:

• At baseline, more patients in the control group suffered from pulmonary diseases. The authors do not address this result in the text.
• Authors do not state whether the patients, caretakers or outcome assessors were blinded to treatment allocation, except for the radiologist who judged the CT scans (this person was blinded to the lab data and clinical findings).
• Sample size was adjusted based on the study results: authors state they halted their study because they did not achieve a clinical response in fifty patients.
• Small sample size (N=50)

Authors conclusion:

The current study showed that there was no clinical benefit in high dose administration of corticosteroid for the treatment of mild to moderate ARDS in patients with COVID-19. However, dexamethasone

administration may shorten the duration of hospitalization.

Horby et al., 2021

Type of study:

randomized, controlled, open-label, trial

Setting:

hospitalized COVID-19 patients; 176 National Health Service (NHS) hospital organizations

Country:

UK

Source of funding:

Conflicts of interest:

The authors have no conflict of interest or financial relationships relevant to the submitted work

to disclose; this work was supported by the National Institute for

Health Research Clinical Research Network

Inclusion criteria:

• Hospitalized
• clinically suspected or laboratory confirmed SARS-CoV-2 infection
• no medical history that might, in opinion of attending clinician, put patient at significant risk
• NOTE: pregnant or breast-feeding women were eligible

Exclusion criteria:

Not further specified

N total at baseline:

Intervention: 2104

Control: 4321

Important characteristics:

Mean age (SD):

I: 66.9y (15.4)

C: 65.8y (15.8)

Male/N (%):

I:  1338/2104 (64%)

C: 2750/4321 (64%)

Intervention group 1.1y older than control group; rate ratios and risk ratios were adjusted for baseline age

Disease severity:

•     mild disease (no supplemental oxygen)

I: 24%, C:24%

•     moderate disease (supplemental oxygen: low flow oxygen, non-rebreathing mask)

I: 61%, C: 60%

•     severe disease (supplemental oxygen: HFNC, CPAP, (NIV), mechanical ventilation).

I: 15%, C: 16%

Usual care + dexamethasone [6 mg given once daily for up to 10 days]

Remark:

In the intervention group, 95% of the patients

received at least one dose of a glucocorticoid.

Usual care

Remark:

In the control group, 8% of the patients received

a glucocorticoid as part of their clinical care.

(This means cross-over between treatment groups took place.)

Length of follow-up:

28 days

Loss-to-follow-up data handling:

Completed follow-up forms were available for 2095 of 2104 patients (99.6%) in the intervention group and 4306

of 4321 patients (99.7%) in the control group.

All information is based on a data cutoff

of December 14, 2020. Information regarding the

primary and secondary outcomes is complete for

99.9% of trial participants.

Mortality, day 28

I:  482/2104 (22.9%)

C: 1110/4321 (25.7%)

Rate ratio 0.83 (95% CI 0.75 to 0.93)

Sub group analysis, by level of respiratory support received at randomization:

Invasive mechanical ventilation

I:  29.3%

C: 41.4%

Rate ratio 0.64 (95% CI 0.51 to 0.81)

Oxygen only

I: 23.3%

C: 26.2%

Rate ratio 0.82 (95% CI 0.72 to 0.94)

No oxygen received

I: 17.8%

C: 14.0%

Rate ratio 1.19 (95% CI

0.91 to 1.55)

Discharge from hospital alive within 28 days

I: 1416/2104 (67.3%)

C: 2748/4321 (63.6%)

RR 1.10 (96% CI 1.03−1.17)

Sub group analysis, by level of respiratory support received at randomization:

Invasive mechanical ventilation

I: 104/324 (32.1%)

C: 157/683 (23.0%)

RR 1.45 (95% CI 1.13−1.85)

Oxygen only

I: 925/1279 (72.3%)

C: 1760/2604 (67.6%)

RR 1.16 (95% CI 1.07−1.25)

No oxygen received

I: 387/501 (77.2%)

C: 831/1034 (80.4%)

RR 0.95 (95% CI 0.84−1.07)

Receipt of invasive mechanical ventilation

(including extra-corporeal membrane oxygenation; among patients not receiving invasive

mechanical ventilation at randomization)

I: 110/1780 (6.2)

C: 298/3638 (8.2)

RR 0.79 (95% CI 0.64–0.97)

Death

(among patients not receiving invasive

mechanical ventilation at randomization)

I: 387/1780 (21.7)

C: 827/3638 (22.7)

RR 0.93 (95% CI 0.84–1.03)

Length of stay (median), days:

I: 12 days

C: 13 days

Safety

Serious adverse events

There were four reports of a serious adverse reaction that was deemed by the investigators to be related to dexamethasone: two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis

Virological outcomes

Viral clearance

not reported

Also available

• Use of ventilation among patients not receiving supplementary oxygen at randomization
• Renal-replacement therapy

Remarks:

Trial design

• This was a randomized controlled trial
• Patients and local members of the trial staff were aware of the assigned treatments.

It is likely that the beneficial

effect of glucocorticoids in severe viral respiratory infections is dependent on the selection of the right dose, at the right time, in the right patient. The phase of COVID-19 of the participants was not specified

Conflict of interests

• Multiple authors reported (financial) support from pharmaceutical or other companies.

Author’s conclusion:

In patients hospitalized with Covid-19, the use of dexamethasone resulted in

lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.

Hydrocortisone

Angus et al.

2020

Type of study:

Ongoing, international, multicenter, open-label randomized clinical trial

Setting:

­An intensive care unit for respiratory or cardiovascular organ support at 121 sites in Australia, Canada, France, Ireland, the Netherlands, New Zealand, the United Kingdom, and the United States.

Source of funding:

This study was funded by multiple (national) research grants.

Inclusion criteria:

• Age >18;
• presumed or confirmed SARS-CoV-2 infection;
• admitted to intensive care unit.

Exclusion criteria:

• Death is deemed to be imminent and inevitable during the next 24 hours AND one or more of the patient, substitute decision maker or attending physician are not committed to full active treatment;
• Patient is expected to be discharged from hospital today or tomorrow;
• More than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to suspected or proven pandemic infection;
• Previous participation in this REMAP within the last 90 days.

N total at baseline:

N = 614

Intervention (I): 137

Intervention (II): 146

Control: 101

Important characteristics:

Age, mean (SD):

I: 60.4y (11.6)

II: 59.5y (12.7)

C: 59.9y (14.6)

Sex, n/N (%) male:

I: 98/137 male (71.5%)

II: 103/146 male (70.6%)

C: 72/101 male (71.3%)

Disease severity:

•     mild disease (no supplemental oxygen)

I: 0%, II: 1%, C:0%

•     moderate disease (supplemental oxygen: low flow oxygen, non-rebreathing mask)

I: 36%, II: 49% C: 48%

•     severe disease (supplemental oxygen: HFNC, CPAP, (NIV), mechanical ventilation).
I: 64%, II: 50%, C: 52%

I: fixed-dose hydrocortisone:

Patients received a fixed dose of intravenous hydrocortisone, 50 mg or 100 mg, every 6 hours for 7 days.

II: shock-dependent hydrocortisone:

intravenous hydrocortisone, 50 mg, every 6 hours while in shock for up to 28 days.

No hydrocortisone

 Up to day 21

Clinical outcomes

In hospital deaths; N (%)

I: 41/137 (30%)

II: 37/141 (26%)

C: 33/101 (33%)

Time to death; adjusted hazard ratio (mean (SD))

I: 0.97 (0.22)

II: 1.01 (0.23)

C: 1 (reference)

adjusted hazard ratio (median (95%CI))

I: 0.94 (0.61 – 1.46)

II: 0.98 (0.63 – 1.54)

C: 1 (reference)

Respiratory support-free days; adjusted odds-ratio (mean (SD))

I: 1.45 (0.34)

II: 1.31 (0.30)

C: 1 (reference)

adjusted odds-ratio (median/95%Crl)

I: 1.42 (0.90 – 2.24)

II: 1.28 (0.81 – 2.00)

C: 1 (reference)

Length of ICU stay; adjusted hazard ratio (mean (SD))

I: 0.93 (0.14)

II: 0.86 (0.13)

C: 1 (reference)

adjusted hazard ratio (median (95% CI))

I: 0.92 (0.68 – 1.24)

II: 0.85 (0.62 – 1.15)

C: 1 (reference)

Length of hospital stay; adjusted hazard ratio (mean (SD))

I: 0.99 (0.16)

II: 0.94 (0.15)

C: 1 (reference)

adjusted hazard ratio (median (95% CI)

I: 0.97 (0.72 – 1.32)

II: 0.93 (0.69 – 1.26)

C: 1 (reference)

Clinical status of patient (day 14); WHO scale

Adjusted odds ratio (mean(SD))

I: 1.33 (0.32)

II: 1.06 (0.26)

C:1 (reference

Adjusted odds ratio (median (95% CI)

I: 1.29 (0.83 to 2.05)

II: 1.03 (0.65 to 1.65)

C: 1 (reference)

Safety

Serious adverse events (>1) N (%)

I: 4/137 (3%)

II: 5/141 (4%)

C: 1/101 (1%)

Virological outcomes

Viral clearance

not reported

Also available

• Organ support-free days
• Organ support-free days among survivors
• Subcomponents of organ support-free days

Definitions:

The WHO scale ranges from 0

(no disease) to 8 (death).

Remarks:

For an additional 11 patients, of whom 5 were in the corticosteroid domain, follow-up data were unavailable. Thus, the final cohort available for outcome analysis comprised 576 participants in the REMAP-CAP severe COVID-19 cohort (whose data are used for covariate adjustment in the primary analysis), of whom 379 were randomized within the corticosteroid domain (after removing 5 patients in the shock-dependent hydrocortisone group whose outcomes were not available).

The study was stopped early,

the probability of benefit with hydrocortisone did not meet the prespecified statistical trigger for a trial conclusion of superiority, and no strategy was determined to be optimal.

Source of funding:

Conflicts of interest:

• Multiple authors reported support from pharmaceutical or other companies.
• The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Authors conclusion:

Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Dequin et al., 2020

CAPECOVID trial = Community-Acquired Pneumonia: Evaluation of

Corticosteroids in Coronavirus Disease

Type of study:

RCT; randomized double-blind sequential trial

Setting:

Multicentre; 9 ICUs; embedded in the ongoing Community-

Acquired Pneumonia: Evaluation of Corticosteroids (CAPECOD) trial.

Start inclusion COVID-19 patients in parent trial: March 7, 2020; ethical committee approval: April 9, 2020.

The sponsor decided to discontinue the trial: July 3, 2020.

Country:

France

Source of funding:

This study was funded by the

French Ministry of Health, Programme Hospitalier

de Recherche Clinique (PHRC) (2014 [CAPE COD parent trial], 2020 [CAPE COVID subtrial]).

Inclusion criteria:

• Age ≥18 years
• admitted to participating ICU for ARDS
• confirmed (RT-PCR) or suspected (suggestive CT chest) COVID-19
• experimental treatment administered < 24 hours of the onset of first severity criterion (see below) or < 48 hours for patients referred from another hospital.
• One of four severity criteria had to be present: 1) need for mechanical ventilation with positive end-expiratory pressure (PEEP) of 5 cm H20 or more; 2) a ratio of PaO2 to fraction of inspired oxygen (FIo2) < 300 on high-flow oxygen therapy with an FIO2 value of at least 50%; 3) for patients receiving oxygen through a reservoir mask, a PaO2:FIO2 ratio less than 300, estimated using prespecified charts; 4) or a Pulmonary Severity Index > 130

Exclusion criteria:

• septic shock
• do-not-intubate orders.

N total at baseline: N = 149

Intervention: 76

Control: 73

Important characteristics:

Age, median (IQR), y:

I: 63.1 (51.5-70.8)

C: 66.3 (53.5-72.7)

Sex, n/N (%) male:

I: 54/76 (71.1%)

C: 50/73 (68.5%)

Groups comparable at baseline.

Hydrocortisone

Continuous intravenous infusion. Initial dose of 200mg/d

Treatment was continued at 200mg/d until day 7 and then decreased to 100 mg/d for 4 days and 50 mg/d for 3 days, for a total of 14 days.

If the patient’s respiratory and general status had sufficiently improved by day 4, a short treatment regimen was used (200mg/d for 4 days, followed by 100mg/d for 2 days and then 50 mg/d for the next 2 days, for a total of 8 days).

[see publication for criteria that allowed considering adaptive scheme)

Adjunctive

treatments could be administered at the discretion of the patients’ primary physicians.

Median duration treatment: 10.5 days

(IQR 6.0 to 14.0)

Placebo (Saline)

Continuous IV infusion

Initial dose of 200mg/d

Treatment was continued at 200mg/d until day 7 and then decreased to 100 mg/d for 4 days and 50 mg/d for 3 days, for a total of 14 days.

If the patient’s respiratory and general status had sufficiently improved by day 4, a short treatment regimen was used (200mg/d for 4 days, followed by 100mg/d for 2 days and then 50 mg/d for the next 2 days, for a total of 8 days).

[see publication for criteria that allowed considering adaptive scheme)

Adjunctive

treatments could be administered at the discretion of the patients’ primary physicians.

Median duration treatment: 12.8 days

(IQR 8.0 to 13.0)

Length of follow-up:

21 days or to death

Loss-to-follow up:

I: 0/76

C: 0/73

1 patient in the intervention group withdrew consent; for the primary outcome this patient was considered to have experienced treatment failure on day 21.

Clinical outcomes

Status on day 21 ((5-item scale)

Death

I: 11 (14.7)

C: 20 (27.4)

Mechanical ventilation

I: 17 (22.7)

C: 17 (23.3)

High-flow oxygen therapy I: 3 (4.0)

C: 0

Low-flow oxygen therapy

I: 1 (1.3)

C: 4 (5.5)

Discharged from ICU

I: 43 (57.3)

C: 32 (43.8)

Need for endotracheal intubation (among patients not intubated at baseline);

I: 8/16 (50%)

C: 12/16 (75%)

Cumulative incidences of prone position sessions (until day 21)

I: 36/76 (47.4%)

C: 39/73 (53.4%)

HR 0.85 (95% CI 0.55 to 1.32)

PaO2:FIO2 ratio measured daily from day 1 to day 7, day 14 and day 21: “Daily evolution of Pa02:FIO2 ratio during the first week and on days 14 and 21 did not significantly differ between the groups (P = .37.”

Safety

Serious adverse events

Three events in intervention group: one episode of cerebral vasculitis possibly related to SARS-CoV-2, one episode of cardiac arrest related to a pulmonary embolism, and one episode of intraabdominal hemorrhage related to anticoagulant therapy for pulmonary embolism. No serious adverse events were attributed to the study treatment.

Virological outcomes

Viral clearance

not reported

Also available

• treatment failure on day 21
• At least 1 episode of nosocomial infection
• At least 1 episode of ventilator-associated pneumonia
• Bacteremia
• Extracorporeal membrane oxygenation / Inhaled nitric oxide

Definitions:

Treatment failure: was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy.

Patient’s status: was determined using a 5-item scale: death, presence in the ICU on mechanical ventilation, high-flow or low-flow oxygen therapy, ICU discharge.

Remarks:

The study was stopped early after release of the RECOVERY trial and might therefore be underpowered

Source of funding:

Conflicts of interest:

• Multiple authors reported support from pharmaceutical or other companies.
• The French Ministry of Health PHRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Authors conclusion:

In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered

to find a statistically and clinically important difference in the primary outcome.

Munch, 2021

Type of study:

Multicentre, parallel-group, placebo-controlled, blinded, centrally randomised, stratified clinical trial

Setting:

Hospital-based, between April 15 and June 16, 2020

Country:

12 trial sites in Denmark

Source of funding:

Funded by the Novo Nordisk Foundation, Grant/Award Number: 0062998 and supported by Rigshospitalet's Research Council, Grant/Award Number: E-22703-06 and Pfizer, Grant/Award Number: 60473019. The funding sources were not involved in designing, conducting, analysing or reporting of the trial.

Conflicts of interest:

Conflicts of interest were transparently and extensively reported.

Patients with COVID-19 and severe hypoxia

Inclusion criteria:

• age ≥ 18 y
• confirmed COVID-19 requiring hospitalisation
• use of one of the following:
  • invasive mechanical ventilation, OR
  • non-invasive ventilation or continuous use of CPAP for hypoxia, OR
  • oxygen supplementation with an oxygen flow of at least 10 L/min independent of delivery system

Exclusion criteria:

• use of systemic corticosteroids
• invasive mechanical ventilation > 48 hrs prior to screening
• invasive fungal infection.
• fertile woman (< 60 y) with positive urine-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

N total at baseline:

Randomized: N = 30

Intervention: N = 16

Control: N = 14

Important characteristics:

Age, median (IQR):

I: 59 y (52-74)

C: 62 y (55-71)

Sex, n/N (%) male:

I: 14/16 (88%)

C: 10/14 (71%)

Unclear whether groups were (statistically) comparable at baseline.

Hydrocortisone i.v. (200 mg/day) for 7 days or until hospital discharge in addition to standard care; continuous infusion over 24 hrs or as bolus injections every 6 hrs (50 mg per bolus)

Placebo (0.9% isotonic saline) i.v. for 7 days or until hospital discharge; continuous infusion over 24 hrs or as bolus injections every 6 hrs (50 mg per bolus)

Length of follow-up:

90 days

Loss-to-follow-up:

I: 0/16 (0%)

Reasons: -

Control: 0/14 (0%)

Reasons: -

The researchers planned to conduct statistical analyses of subgroup differences on the primary outcome (i.e. days alive without life support at day 28) in the ITT population, but refrained from this due to the reduced sample size.

Clinical outcomes

Mortality

Days alive without life support at day 28

Days, median (IQR)

I: 7 (2-24)

C: 10 (3-26)

aMD -1.1 (95% CI -9.5-7.3)

Days alive without life support at day 90

Days, median (IQR)

I: 41 (6-86)

C: 72 (52-88)

aMD -14.7 (95% CI -40.4-10.9)

All-cause mortality at day 28

n/N (%)

I: 6/16 (38%)

C: 2/14 (14%)

RR 2.63 (95% CI 0.74-16.03)

All-cause mortality at day 90

n/N (%)

I: 7/16 (44%)

C: 3/14 (21%)

RR 2.04 (95% CI 0.71-8.16)

Days alive and out of hospital at day 90

Days, median (IQR)

I: 31 (8-78)

C: 53 (42-68)

aMD -6.5 (95% CI -29.6-16.7)

Duration of hospitalization

Not reported.

Time to symptom resolution

Not reported.

Respiratory support

Not reported.

Safety

≥ 1 serious adverse reactions

n/N (%)

I: 1/16 (6%)

C: 0/14 (0%)

Virological outcomes

Viral clearance

Not reported.

Definitions:

-

Remarks:

The researchers planned to randomise 1000 adult patients with COVID-19 and severe hypoxia in Denmark, Sweden, Switzerland and India. The trial was commenced on April 15, 2020; paused on June 16, 2020; and terminated early on September 4, 2020, after 30 patients had been enrolled at 12 trial sites in Denmark. The trial was terminated very quickly after starting enrollment, due to unexpected (at trial design) inability to enroll participants.

Authors conclusion:

In this early terminated randomised clinical trial of adult patients with COVID-19 and severe hypoxia, we were unable to provide any precise estimates on the benefits and harms of hydrocortisone versus placebo for any outcomes as only 3% of the planned sample size had been enrolled.

Methylprednisolone

Jeronimo, et al.,

2020

Type of study: RCT

Setting: a tertiary care facility in Manaus, Brazil

Country: Brazil

Diagnosis COVID-19:

Hospitalized patients with 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)

Inclusion criteria:

• Age 18 years or older
• SpO2 ≤ 94% at room air OR in use of supplementary oxygen OR required IMV.

Exclusion criteria:

• history of hypersensitivity to MP
• HIV/AIDS
• chronic use of corticosteroids or immunosuppressive agents
• pregnant or breastfeeding
• decompensated cirrhosis
• chronic renal failure.

N total at baseline:

N = 397

Intervention: 195

Control: 202

Important characteristics:

Age, mean (SD):

I: 54 (15)

C: 57 (15)

Sex, n/N (%) male:

I: 68/194 (35.1)

C: 71/199 (35.7)

Disease severity:

Invasive mechanical ventilation n/N (%):

I: 66/194 (34%)

C: 67/199 (33.7%)

Non-invasive oxygen therapy n/N (%):

I: 98/194 (50.5%)

C: 90/199 (45.2%)

Groups comparable at baseline

Intravenous sodium succinate MP (0.5 mg/kg), twice daily for 5 days

Remark:

all patients meeting ARDS criteria used pre-emptive intravenous ceftriaxone (1 g 2× for 7 days) plus azithromycin (500 mg 1× for 5 days) or clarithromycin (500 mg 2× for 7 days), starting on Day 1.

Intravenous placebo (saline solution) (0.5 mg/kg), twice daily for 5 days

Up to 28 days or to death.

Clinical outcomes

28-day mortality, %

I: 72/194 (37.1%)

C: 76/199 (38.2%)

P-value: 0.629

7-day mortality, %

I: 32/194 (16.5%)

C: 47/199 (23.6%)

P-value: 0.089

14-day mortality, %

I: 53/194 (27.3%)

C: 63/199 (31.7%)

P-value: 0.290

Need for invasive mechanical ventilation until day 7, n/N (%):

I: 18/93 (19.4%)

C: 16/95 (16.8%)

Proportion of patients with oxygenation index, PaO2/FiO2, <100 until day 7, n/N (%):

I: 21/60 (35%)

C: 16/51 (25.5%)

Length of hospitalization, days, median (IQR):

I: 10 (7-13)

C: 9 (7-12)

Safety

not reported

Virological outcomes

Presence of viral RNA in the naso/oropharyngeal swab on day 5, %

I: 69/144 (47.9%)

C: 66/139 (47.5%)

P-value: 0.942

Presence of viral RNA in the naso/oropharyngeal swab on day 7, %

I: 61/117 (52.1%)

C: 50/95 (52.6%)

Also available

• pulmonary fibrosis after day 7
• bronchiolitis obliterans with organizing pneumonia
• positive blood culture on day 7
• need for insulin therapy until day 28
• sepsis until day 28

Remarks:

limitations, including that it: (1) was a single-center study; (2) had a low sample size to estimate small differences between the arms and subgroup analyses; (3) had high overall mortality as compared to other settings; and (4) included late administration of the drug in some patients.

Source of funding:

Conflicts of interest:

• F. G. N., M. L. N., F. T. M. C., W. M. M., and M. V. G. L. are research fellows from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico. All other authors report no potential conflicts
• The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Authors conclusion: “In conclusion, the use of MP during only 5 days in hospitalized patients with COVID-19 was not sufficient to improve prognosis, as opposed to RECOVERY trial, in which dexamethasone was successfully used for 10 days. Our exploratory analysis showed that MP reduces mortality in hospitalized patients older than 60 years with COVID-19. Caution is needed in the use of steroids in less severe patients, as a trend towards more harm was seen in the lower age group.”

Edalatifard, 2021

Type of study:

RCT; single-blind, two-arm parallel, randomized, controlled trial

Setting:

April 20, till Jun 20, 2020; multi-center; 2 university hospitals, Tehran

Country:

Iran

Source of funding:

This study was supported by a grant from Deputy of Research, Tehran University of Medical Sciences

Severe hospitalized patients with confirmed COVID-19

Diagnosis COVID-19:

1. Positive RT-PCR for SARS-CoV-2 in nasopharyngeal swab or sputum samples

2. Abnormal CT scan finding (bilateral, subpleural, peripheral ground-glass opacities) with oxygen saturation <90% at rest. Early pulmonary phase:

start of pulmonary involvement including hypoxia (SO2<93%) tachypnea (RR> 18) and little dyspnea and based on CT scan findings.

Inclusion criteria:

• Age 18 years or older;
• Confirmed COVID-19 with blood oxygen saturation <90%), elevated C-reactive protein (CRP >10), interleukin (IL)-6 (>6) at early pulmonary phase of disease before connecting to ventilator and intubation
• agreed to give informed consent

Exclusion criteria:

• intolerant or allergic to any therapeutic agents
• Pregnant or lactating women
• blood oxygen saturation <75%
• positive pro-calcitonin (PCT)
• 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.

N total at baseline:

N = 68

Intervention: 34

Control: 34

Important characteristics:

Age, mean ± SD:

I: 55.8y ± 16.35

C: 61.7y ± 16.62

Sex, n/N (%) male/female:

I: 24 (70.6%)/ 10 (29.4%)

C: 15 (53·5%)/ 13 (46.4%)

Days from illness onset to

Hospitalization, mean SD:

I: 6.7 ± 2.92

C: 6.9 ± 3.09

Disease severity:

Need for oxygen therapy:

Nasal Cannula

I: 4 (11.8%)

C: 9 (32.1%)

Simple Mask

I: 5 (14.7%)

C: 2 (7.1%)

Reserve Mask

I: 12 (35.3%)

C: 6 (21.4%)

Non-invasive ventilation

I: 13 (38.2%)

C: 10 (35.7%)

Baseline group comparability: More males in the intervention group. More nasal cannula in control group, more simple mask and reserve mask in intervention group.

Methylprednisolone pulse + standard of care

(intravenous

injection, 250mg/day for 3 days)

Standard of care, no methylprednisolone or other glucocorticoids

Standard care: Hydroxychloroquine sulfate, Lopinavir, and Naproxen

Length of follow up:

For most outcomes 3 days of treatment and discharge time; primary outcomes:

“All patients were followed-up from day 0 to day 3, improvement, hospital discharge or death and 1 week after hospital discharge”

Loss to follow-up:

I: 0 (0%)

C: 0 (0%), n=6 excluded, received intervention therapy

Clinical outcomes

Death, n (%)

I: 2 (5.9)

C: 12 (42.9)

Recovery, n (%)

I: 32 (94.1)

C: 16 (57.1)

Survival rate,

Kaplan–Meier Log-rank test:

HR 0.293 (95% CI 0.154–0.556).

Need for oxygen therapy, day 3, n:

I: 28/34 (82.4%)

C: 26/28 (92.8%)

Safety

Severe adverse events

I: 2 (5.8%)

C: 2 (7.1%)

Adverse events

Infection, n (%)

I: 1 (2.9%)

C: 0

Edema, n (%)

I: 1(2.9%)

C: 0

Shock, n (%)

I: 0

C: 2 (7.1%)

Digestive bleeding, n (%)

I: 0

C: 0

Others

I: 0

C: 0

Of which events related to study treatment

I: 0

C: 0

Psychiatric or delirium events

I: 0

C: 0

Virological outcomes

Viral clearance

not reported

Also available

• Laboratory findings and clinical symptoms before and after treatment
• Time to event (discharge or death)

Time to improvement

Definitions:

Improvement: was defined as Borg score >3, improved dyspnoea, no fever for 72 h, SpO2 >93%, tolerated oral regime, normal urinary output and reduced CRP level without any treatment side-effects.

Remarks:

• 6 patients in the control group received intervention treatment and were excluded from analysis
• Treating physicians were not blinded to treatment
• Follow up short compared to other studies
• There are several other limitations in this study, including the possible existence of bias, single-blind design of the study, lack of follow-up to identify late adverse events and limited sample size

Authors conclusion:

Our results suggest that methylprednisolone pulse could be an efficient therapeutic agent for

hospitalized severe COVID-19 patients at the pulmonary phase.

Source of funding:

Conflicts of interest:

• The authors declare that they have no competing interests
• The funder of the study had no role in study design, data collection, data analysis, data

interpretation or writing of the report.

Corral-Gudino et al.,

2021

Type of study:

Partially randomized open-label controlled trial

Setting:

5 hospitals in Spain in April-May 2020

Country:

Spain

Source of funding:

The authors received no specific funding for this work.

Inclusion criteria:

• Over 18 years of age
• Hospitalized
• laboratory confirmed diagnosis of SARS-CoV2 infection
• Symptom duration ≥7 days
• Radiological evidence of lung disease in chest X-ray or CT-scan
•  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)
•  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:

• intubated or mechanically ventilated
• hospitalized in the ICU
• treated with corticosteroids or immunosuppressive drugs at the time of enrolment
• chronic kidney disease on dialysis
• pregnant
• refused to participate

N total at baseline:

N = 85,

(22 received MP according to clinician’s preference, and 64 were randomized)

Intervention: 35

Control: 29

Important characteristics:

Age, mean (SD):

I: 73 (11)

C: 66 (12)

Mean diff: -7 (95% CI: -13 to -2)

Sex, n/N (%) male:

I: 23/35 (68%)

C: 26/29 (55%)

Mean diff: -11% (95% CI: -33 to 13)

Groups comparability at baseline:

Those in the intervention group were slightly older, but the baseline characteristics were otherwise very similar across groups.

The use of lopinavir/ritonavir was slightly more frequent in the control arm.

Methylprednisolone (MP)

In addition to SOC, patients in the experimental group received intravenous methylprednisolone (MP) 40 mg, twice a day, for 3 days and then 20 mg, twice a day, for 3 more days.

The clinical teams freely prescribed Interleukin-blocking agents and other therapies, as indicated.

Standard of care (SOC)

SOC included symptomatic treatment with acetaminophen, oxygen therapy, thrombosis prophylaxis with low molecular weight heparin, and antibiotics for co-infections. Azythromycin, hydroxychloroquine and lopinavir plus ritonavir were frequently prescribed.

Up to 28 days or to death.

Clinical outcomes

Mortality at 28 days:

I: 7/35 (20%)

C: 5/29 (17%)

Intention-to-treat

Primary composite outcome:

Relative risk: 0.68 (0.37-1.26), p=0.25

Escalation to ICU admission

I: 6/35 (17%)

C: 8/29 (28%)

RR: 0.85 (95% CI: 0.27 to 2.66)

Progression of respiratory insufficiency that required non-invasive ventilation (NIV)

I: 10/35 (29%)

C: 7/29 (24%)

Safety

Adverse events

Hyperglycaemia:

I: 9/35 (26%)

C: 0/29 (0%)

RR: 7.70 (95% CI: 1.10 to 40.4)

Nosocomial infection

I: 5/35 (14%)

C: 1/29 (3%)

RR: 2.12 (95% CI: 0.31 to 14.38)

Virological outcomes

not reported

Also available

• Per protocol analysis
• % variation in biochemical markers of inflammation from baseline to six days after randomization

Definitions:

Primary composite outcome: In-hospital all-cause mortality OR escalation to ICU admission OR progression of respiratory insufficiency that required NIV

Remarks:

- Initial sample size was 90 patients in each study arm. In this paper the results of the interim analysis, which was planned a priori after inclusion of one-half of the patients, to avoid delaying the communication of clinically useful data in the current pandemic scenario.

- Patients were censored at hospital discharge or day 15 after inclusion.

- 85 patients were analysed; 22 received MP according to the clinician’s preference, and 63 were randomized. Although allowed by design, no patient was included in the control arm by clinician’s preference.

- More than 90% of the patients took hydroxychloroquine and/or azithromycin during hospital admission.

- According to the authors, a purely randomized design appeared difficult to follow, and it could likely had implied a high risk of inclusion bias. So, we adopted a pragmatic mixed preference/ randomized design.

Conflicts of interest:

All authors declare that they have no competing interests

Authors conclusion:

In summary, although the study was terminated before achieving the complete sample size and no significant differences in ITT analysis were found, our PP analysis suggests that MP most likely has a clinically relevant effect in reducing the risk of developing severe respiratory insufficiency and ARDS, thus helping clinicians tailor therapy in non-mechanically ventilated patients with lung disease and systemic inflammation. These data should be interpreted with caution along with the outcomes of other trials of corticosteroid use in COVID-19 patients

Solanich, 2021

Type of study:

Randomized, single-center, open-label, phase II trial

Setting:

One public hospital for adults, between 1 April and 2 May 2020

Country:

Spain

Source of funding:

 COVID-19 funding from the Departament de Salut de la Generalitat de Catalunya

Conflicts of interest:

No conflict of interest

Severe COVID-19 patients with lung injury and systemic hyperinflammatory syndrome

Inclusion criteria:

• COVID-19 confirmed by nasopharyngeal RT-PCR
• New pulmonary infiltrates
• Respiratory failure (PaO₂/FiO₂ <300 or SpO₂/FiO₂ <220)
• High analytical inflammatory parameters: CRP >100 mg/L, D-Dimer >1000 µg/L, ferritin > 1000 µg/L

Exclusion criteria:

• Life expectancy ≤254h
• Glomerular filtration ≤30 ml/min/1.73m²
• Leukopenia ≤4000 cells/µl or other immunosuppression conditions
• Concomitant potential serious infections
• Contraindication for corticosteroids or tracolimus
• Known hypersensitivity to study drugs, their metabolites or formulation excipient
• Previous participation in RCT <3 months before

N total at baseline:

N = 55

Intervention: 27

Control: 28

Important characteristics:

Age, mean (SD):

I: .61.5 y (13.9)

C: 64.8 y (12.1)

Sex, n/N (%) male:

I: 23/27 (85.2%)

C: 21/28 (75.0%)

Disease severity, mean (SD):

Defined by ordinal scale

I: 5 (5-5)

C: 5 (5-6)

Score 5:

I: 23/27 (85.2%)

C: 16/28 (57.1%)

Score 6:

I: 4/27 (14.8%)

C: 12/28 (42.9%)

Groups are not completely balanced, especially regarding time between symptom onset and randomization, the need for non-invasive ventilation or high-flow oxygen devices, corticosteroids use, CRP and creatinine kinase.

Methylprednisolone pulses and tracolimus added to standard of care

methylprednisolone pulses of 120 mg/day had to be administered on 3 consecutive days after randomization (if not previously administered). The administration of higher doses or longer duration of corticosteroids was allowed if their treating physicians considered it appropriate. Tacrolimus starting dose was 0.05 mg/kg (Adoport®) twice daily. Patients using lopinavir-ritonavir received 0.2 mg (Modigraf®) every 48 h. Thereafter, tacrolimus dosing was individualized through therapeutic drug monitoring to achieve blood trough levels of 8–10 ng/ml. In addition, patients in the experimental arm could receive standard of care (SoC) for their management in accordance with treating physicians.

Standard of care

SoC included measures of supplemental oxygen and respiratory support, fluid therapy, antipyretic treatment, postural measures, low molecular weight heparins, and could also include treatments with unproved antiviral (lopinavir-ritonavir, hydroxichloroquine, etc.) or immunosuppressive (any regimen of corticosteroids, tocilizumab, anakinra, etc.) drugs, or those necessary at the discretion of the treating physician, except for cyclosporine and/or tacrolimus.

Length of follow-up: 56 days

Loss-to-follow-up:

Intervention: 3/27 (11.1%)

Reasons (describe)

n=3: treatment compliance

Control: 2/28 (7.1%)

Reasons (describe)

n=2: deceased with <5 days of follow-up

Incomplete outcome data:

Some incomplete data regarding viral load, however, reasons not clear.

Clinical outcomes

COVID-19-related mortality (28 day)

I: 3/27 (11.1%)

C: 4/28 (14.3%)

OR: 0.76 [0.13-4.02]

COVID-19-related mortality (56 day)

I: 4/27 (14.8%)

C: 4/28 (14.3%)

OR: 1.04 [0.21-5.13]

All-cause mortality (28 day)

I: 4/27 (14.8%)

C: 6/28 (21.4%)

OR: 0.65 [0.14-2.67]

All-cause mortality mortality (28 day)

I: 5/27 (18.5%)

C: 6/28 (21.4%)

OR: 0.84 [0.21-3.28]

Also reported: mortality rates at day 10, time to COVID-19 related death, and time to all-cause death.

Duration of hospitalization

I: 13.0 (8.5-21.0)

C: 14.0 (9.0-22.5)

Discharge at day 65

I: 21/27 (77.8%)

C: 21/28 (75.0%)

OR: 1.16 [0.32-4.28]

Time to symptom resolution:

clinical stability at 56 days, n/N (%):

I: 21/27 (77.8%)

C: 22/28 (78.6%)

OR: 0.96 [0.25-3.61]

Time to clinical stability, median days (IQR):

I: 10 (7-13)

C: 11 (8-18.8)

HR=0.73 (95% CI 0.39-1.37)

Also reported: clinical stability at 10 and 28 days, ordinal scale at day 5, day 10, day 28 and day 58, time to body temperature normalization, PaO₂/FiO₂ >400 or SpO₂/FiO₂ >300, and respiratory rate <24 bpm.

Respiratory support

Duration of oxygen support (days)

I: 11.0 (8.0-19.5)

C: 13.0 (7.75-23.0)

p=0.953

High-flow or ventilatory support therapies

I: 14/27 (51.9%)

C: 18/28 (64.3%)

p=0.509

Duration of high-flow or ventilatory support (days)

I: 8.00 (5.0-27.2)

C: 6.5.0 (4.25-14.2)

p=0.303

Safety

Adverse events

I: 23/27 (85.2%)

C: 23/28 (82.1%)

Serious adverse events

I: 9/27 (33.3%)

C: 10/28 (35.7%)

Virological outcomes

SARS-CoV-2 positive test at day 56

Upper respiratory tract samples at day 0

I: 24/24, 100%

C: 20/20, 100%

Upper respiratory tract samples at day 28

I: 4/19, 21.1%

C: 2/18, 11.1%

Upper respiratory tract samples at day 56

I: 1/17 (5.8%)

C: 1/20 (5.0%)

Blood samples

I: 1/22 (4.5%)

C: 2/19 (10.5%)

OR/RR not reported

Also reported: positive test at day 28, viral load.

Definitions:

Clinical stability was defined as fulfilling all of the following criteria for 48 consecutive hours: body temperature ≤37.5°C; PaO2/FiO2 >400 and/or SpO2/FiO2 > 300; and respiratory rate ≤ 24 rpm.

Treatment failures were defined as: 1) not hospitalized and no limitations of activities; 2) not hospitalized, with limitation of activities, home oxygen requirement, or both; 3) hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization was extended for infection-control or other nonmedical reasons); 4) hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (related to Covid-19 or to other medical conditions); 5) hospitalized, requiring any supplemental oxygen; 6) hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices; 7) hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); and 8) death.

Remarks:

• Groups are not comparable on baseline (see patient characteristics)

Authors conclusion:

The combined use of methylprednisolone pulses and tacrolimus, in addition to the SoC did not significantly improve the time to clinical stability or other secondary outcomes compared with SoC alone in hospitalized patients with severe COVID-19. Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC. No relevant differences were observed in the clearance of the virus or in the rate of adverse events between the two groups. The reason why the largest and longest corticosteroid doses were used in the control group remains unclear.

Tang, 2021

Type of study:

prospective, multicentre, single-blind, clinical RCT

Setting:

Conducted between February and April 2020 in respiratory departments or infectious disease department of 7 tertiary hospitals in Beijing and Hubei province of China.

Country:

China

Source of funding:

Beijing Municipal Administration

of Hospitals’ Mission Plan, China; Excellence

Program of Beijing Clinical Key Specialty (2018); Novel Coronavirus

Pneumonia Key Technology Research and Development

Funding of Beijing Municipal Administration of Hospitals.

The authors declare no conflict of interest.

Pfizer Manufactoring Belgium NV produced the methylprednisolone, but was not involved in analysis of the results.

Patients with COVID-19 pneumonia admitted to general wards for less than 72h.

Inclusion criteria:

• Laboratory confirmed SARS-CoV-2 infection and had pneumonia;
• Age ≥ 18 y;
• Admitted to general wards for less than 72 h;
• Able to sign informed consent.

Exclusion criteria:

• Severe immunosuppression;
• Pregnant or breastfeeding women;
• Corticosteroid needs for other diseases;
• Refractory hypertension;
• Epilepsy or delirium;
• Glaucoma;
• Active gastro-intestinal bleeding within 3 months;
• Refractory hypokalemia;
• Secondary bacterial or fungal infection;
• Unwilling or unable to participate or complete the study;
• Participation in other studies

N total at baseline:

N = 86

Intervention: 43

Control: 43

Important characteristics:

Age, median (IQR):

I: 57 y (49-67)

C: 55 y (38-65)

Sex, n/N (%) male:

I: 21/43 (48.8%)

C: 20/43 (46.5%)

Groups were comparable at baseline, with the exception of the number of patients who showed the symptom “sputum”. In the intervention group, more patients showed this symptom (I: 17 vs. C: 6).

1 mg/kg per day of methylprednisolone

dissolved in 100 mL 0.9% normal saline, administered intravenously for 7 days + standard care

100 mL 0.9% normal saline administered intravenously + standard care

Length of follow up: 14 days

Loss to follow-up:

I: 0/43 (0%)

C: 0/43 (0%)

Clinical outcomes

In-hospital mortality, n (%)

I: 0 (0%) / 43

C: 1 (2.3%) / 43

OR 0.977 [0.933 to 1.023]

P = 0.314

Duration of hospitalization, median (IQR), days

I: 17 (13–22)

C: 13 (10–20)

HR 1.300 [0.844 to 2.002]

P = 0.235

ICU admission, n (%)

I: 2 (4.8%) / 43

C: 2 (4.8%) / 43

OR 1.000 [0.134 to 7.442]

P = 1.000

Clinical deterioration 14 days after randomization, n (%)

I: 2 (4.8%) / 43

C: 2 (4.8%) / 43

OR 1.000 [0.134 to 7.442]

P = 1.000

Clinical cure 14 days after randomization, n (%)

I: 22 (51.2%) / 43

C: 25 (58.1%) / 43

OR 1.326 [0.566 to 3.106]

P = 0.516

Time from randomization to clinical cure, median (IQR), days

I: 14 (10–19)

C: 12 (9–17)

HR 1.043 [0.673 to 1.617]

P = 0.850

Need for respiratory support

The median duration of hospitalization was 17 days (IQR: 13-22) and 13 days (IQR: 10-20) in the methylprednisolone and placebo groups, respectively. No significant differences between groups were found (p=0.314, HR = 1.3 [95% CI 0.84-2.00]).

Safety

Adverse events

Not reported

Virological outcomes

Time from virus shedding of SARS-CoV-2, median (IQR), days

I: 11 (6–16)

C: 8 (2–12)

HR 1.782 [1.057 to 3.003]

P = 0.030

Definitions:

• Clinical deterioration: patient met at least one of the following criteria: the clinical symptoms and signs continue to deteriorate, new pulmonary or extrapulmonary lesions appear, the chest computed tomography indicates the progress, or the patient is transferred to the ICU or is dead.
• Clinical cure: patient met all of the following criteria: the clinical symptoms and signs of COVID-19 improved or alleviated (body temperature for 3 consecutive days, respiratory symptoms improved significantly, and computed tomographic images showed obvious absorption of bilateral extensive ground-glass opacification and/or consolidation), and no additional or alternative treatments were needed.
• Virus shedding: SARS-CoV-2-negative result of the nucleic acid tests from throat swabs for 2 consecutive times (sampling interval of at least 1 day). RT-PCR was used to test SARS-CoV-2.

Remarks:

• Pfizer pharmaceuticals produced the intervention drug.
• Single-blinded RCT: physicians were aware of treatment randomization
• Trail was terminated prematurely (because the number of patients with COVID-pneumonia decreased).

Authors conclusion:

Due to early termination of this trial, most outcomes were difficult to estimate because of the low statistical power. However, the short-term early use of corticosteroid could suppress the immune cells, which may prolong SARS-CoV-2 shedding in patients with COVID-19 pneumonia, especially for the patients without acute respiratory failure. It was suggested that corticosteroids

should not be added to standard therapy as a general treatment for the patients of COVID-19 patients; moreover, it should be evaluated according to the severity

and necessity. The interpretation still needs to be further verified by a large sample size and randomized clinical

trials.

First author, year

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Dexamethasone

Tomazini et al. 2020

The randomization list was generated by the trial statistician, not involved in patient care or enrolment, using the R software. The list comprised random

blocks of two and four, unknown to researchers and stratified at center level and was uploaded and implemented in the on-line web-based system used for randomization data collection.

Unlikely

The randomization list was generated by the trial statistician, not involved in patient care or enrolment, using the R software.

The group treatment was disclosed to the investigator only after all information regarding patient enrolment was recorded in the online system.

Likely

Physicians, patients, and individuals who assessed the outcomes were not blinded for the assigned treatment

Likely

Physicians, patients, and individuals who assessed the outcomes were not blinded for the assigned treatment

Likely

Physicians, patients, and individuals who assessed the outcomes were not blinded for the assigned treatment

Unlikely

All predefined outcome measures were reported

Unlikely

All patients were included in the primary analysis. There was no loss to follow-up, and data on the primary outcome, mortality within 28 days, clinical status at day 15, ICU-free days at 28 days, and mechanical ventilation duration were available for all patients.

Unlikely

ITT analysis performed.

Jamaati, 2021

Computerized

The selected patients were allocated to either the dexamethasone group or the control group by block randomization. Ten blocks were generated by the Online Randomizer website. Each block included five patients; of these, two patients were assigned to the dexamethasone group and three patients were assigned to the control group or vice versa.

Unclear

It is unclear whether allocation of treatment was concealed to the patients and caretakers.

Unlikely

The authors do not report whether the patients were blind to the randomization. However, it is not expected that patients influenced the reported outcome measures (need for invasive mechanical ventilation, death rate, length of hospital / ICU stay, and radiological changes in the CT scan).

Unclear

The authors do not report whether any blinding occurred. This may have affected the more subjective outcome measures such as duration of hospital stay, and whether ventilation was started or maintained.

Unlikely

The authors report that the radiologist who assessed the CT scans was blinded to the lab data and clinical findings.

Unlikely

All outcome measures stated in the methods section were reported in the results.

Unlikely

No patients seem to have been lost to follow up (except for those who died).

Unlikely

No mention of ITT analysis, however the participants seem to be analyzed as allocated.

Horby et al., 2021

Randomization was performed

with the use of a Web-based system with concealment

of the trial-group assignment

Unlikely

Adequate concealment

“webbased

system randomization with concealment of the trial-group assignment”.

Likely

Patients not blinded, primary outcome not susceptible for bias (death)

Likely

Study staff not blinded to allocated treatment

Likely

Study staff not blinded to allocated treatment

Unlikely

Relevant outcomes reported; protocol and analysis plan available

Unlikely

Completed follow-up forms were available for 2095 of 2104 patients (99.6%) in the intervention group and 4306 of 4321 patients (99.7%) in the control group.

All information is based on a data cut-off

of December 14, 2020. Information regarding the primary and secondary outcomes is complete for 99.9% of trial participants.

Unlikely

Analyses performed according to intention-to-treat protocol

Hydrocortisone

Angus et al. 2020

Randomization will be conducted through a password-protected, secure website using a central, computer-based randomization program.

Unlikely

Randomization will be at the patient level

and occur after data necessary to implement the inclusion and exclusion criteria have been entered into the secure randomization website. The RAR will occur centrally as part of the computerized randomization process. Sites will receive the allocation status and will not be informed of the randomization proportions.

Unclear

Not reported in the study

Unlikely

The default position within the REMAP is that treatments determined by randomization will

be provided on an open-label basis. However, the blinding of treatment status is not precluded within the REMAP. If required, details related to blinding of interventions will be

specified in the DSAs.

Unlikely

The primary outcome of all-cause mortality censored at 90 days is not subject to ascertainment bias. Wherever possible, trial management personnel, who are blinded to allocation status, will conduct any follow up after discharge.

Unlikely

Wherever possible, trial management personnel, who are blinded to allocation status, will conduct any follow up after discharge.

Unlikely

Patients missing the

primary end point (n = 5) were ignored; there was no imputation

of missing primary (or secondary) end point values. A patient who survived to hospital discharge was assumed

to be free of organ support through 21 days (last status carried

forward).

Unlikely

Analysis of the primary outcome was then repeated in a second model using only data from those patients enrolled in the corticosteroid domain with no adjustment for assignment to interventions in other domains. Although using less information, this analysis is more typical for an RCT. Further secondary analyses explored the effects of excluding patients who were ruled out for COVID-19 (defined as documented negative test results for SARS-CoV-2 infection and no positive test results), of excluding adjustment for site and time epoch, and of combining the fixed-dose and shock-dependent hydrocortisone groups.

Dequin et al., 2020

Computerized

“Randomization was centralized and performed electronically.

Allocation sequences were generated in a 1:1 ratio by a computer-generated random number using a blocking schema; the range of block sizes remains confidential until the completion of the parent trial. Randomization was stratified by center and by use of mechanical ventilation at the

time of inclusion.”

Likely

Randomization stratified by center

Unlikely

Patients in placebo group in identical protocol

Unlikely

“Both hydrocortisone and placebo were provided in industrially

prepared packaging (Serb Specialty Pharmaceuticals).”

Unclear

Unlikely

Trial registered; all relevant outcomes reported

Unlikely

1 patient in the intervention group withdrew consent; this patient was considered to have experiences treatment failure on day 21 (primary outcome)

Unlikely

Analyses performed according to intention-to-treat protocol

Munch, 2021

Computerised

Participants were randomised (1:1) using a centralised and web-based randomisation system at the Copenhagen Trial Unit (CTU. The randomisation was performed according to a computer-generated allocation sequence, stratification variables, and varying block sizes.

Unlikely

The allocation sequence was only known by the data

manager at the CTU.

Unlikely

Participants were blinded to treatment allocation.

Unlikely

Clinical staff members were blinded to the allocation.

Unlikely

Management Committee, investigators, trial site staff registering outcome data and the trial statistician were blinded to the allocation.

Unlikely

All outcome measures described in the methods are reported in the results.

Unlikely

No participants were lost to follow-up.

Unlikely

All analyses were done in the intention-to-treat population, defined as all randomised participants for whom there were consent to use data.

Methylprednisolone

Edalatifard et al., 2021

Method not described

“the patients randomly

allocated in control (n=34) and intervention group (n=34), in a 1:1 ratio by block

randomization method.”

Unclear

not described

Unlikely

Patients were blinded to treatment

Likely

“ Physicians and

clinicians team know about the medicine and intervention groups”

Likely

“ Physicians and

clinicians team know about the medicine and intervention groups”

Unlikely

Relevant outcomes reported

Trial registered:

Iranian Registry of Clinical Trials on 15

April 2020 (IRCT ID: IRCT20200404046947N1

Likely

34/34 (100%) of patients of the intervention and 28/34 (82.4%) of patients of the control group included in analysis

Likely

6 patients (17.8%) discontinued treatment of control group and received intervention. They were excluded from the analysis.

Analyses performed according to intention-to-treat protocol

Jeronimo et al., 2020

An independent statistician prepared an electronically generated

randomization list with 14 blocks of 30 participants

per block,

Unlikely

The list was accessible only to nonblinded pharmacists

in the study. Participants were randomized by the study

pharmacist to their designated treatment regimen at the time

of inclusion and were subsequently identified throughout the

study only by their allocated study number.

Unlikely

Patients were considered to be blinded for the interventional drug

Unclear

No blinding of care providers

Unlikely:

Radiologists and other assessors were blinded

Unlikely

Primary outcome was mortality

Unlikely

Low loss to follow up:

I: 0.5%
C: 1%

Unlikely

A modified and non-modified intention-to-treat analyses was conducted

Corral-Gudino et al., 2021

Patients were randomized based on a spreadsheet that transformed every medical record number into a group allocation using a concealed mathematical formula

Partly randomized; i.e. some participants received treatment according to the clinician’s preference, the other participants were randomized.

If the clinical team decided that a strong preference for glucocorticoid therapy existed, the patient was allocated to the preference arm. Otherwise, the patient was randomized (1:1) and allocated to the MP or control arm accordingly..

Unclear

Note: allocation concealment not described.

allocation.

Unclear

Note: Blinding of participants was not described

Unclear

Note: Blinding of care providers was not described

Unclear

Note: Blinding of outcome assessors was not described

Unclear

Note: Protocol not available

Unclear

Note: Loss to follow-up was not reported

Likely

Note: In the intention-to-treat analysis, only patients who received at least one dose of treatment were included in the treatment arm.

Tang, 2021

Computerized

Randomization was

stratified by the statistician of the leading site, who produced computer-

generated block randomization lists with a block size of 4

patients.

Unlikely

Allocation of treatment seems to have been concealed properly.

Unlikely

Patients were blind to treatment allocation.

Likely

Care providers were not blind to treatment allocation. Therefore, they could have biased the outcome measures that are prone to subjectivity, such as the duration of hospitalization and ICU admission.

Unlikely

It is unlikely that care providers biased objective outcome measures such as mortality, clinical deterioration or clinical cure, and virus shedding.

Unlikely

During the study, data collection and end point judgement were blinded, and the statisticians were also blinded during the statistical analysis.

Unlikely

All outcome measures stated in the methods section were reported in the results.

Unlikely

No patients were lost to follow up.

Unlikely

Authors indicate that an ITT was not necessary and the included patients seem to be analyzed as allocated.

Solanich, 2021

Computerized

Patients were randomized using the RedCap, a secure web application for building and managing electronic case report forms (eCRF). Patients were randomly (1:1) assigned to one of the study arms with no baseline stratification.

Unclear

No information on concealment

Likely

Open-label RCT

Likely

Open-label RCT

Unlikely

The IDIBELL Biostatistical Unit performed the analysis and analysts were blinded to the treatment received by patients (intervention vs. usual care)

Unlikely

All outcomes were reported in main article of appendix

Unlikely

Similar loss to follow-up, no indications for bias

Unlikely

Except for outcome on viral load, but no comparisons were done.