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Table 4a. Systemic Corticosteroids: Selected Clinical Data

Last Updated: December 16, 2021

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for systemic corticosteroids. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations. Unless stated otherwise, the clinical trials listed below included participants aged 18 years or older.

Table 4a. Systemic Corticosteroids: Selected Clinical Data
Methods Results Limitations and Interpretation
RECOVERY: Open-Label RCT of Dexamethasone in Hospitalized Patients With COVID-19 in the United Kingdom1
Key Inclusion Criteria:
  • Hospitalized with suspected or laboratory-confirmed SARS-CoV-2 infection

Key Exclusion Criteria:

  • Physician determination that risks of participation too great based on patient’s medical history or an indication for corticosteroid therapy outside of the study

Interventions

  • DEX 6 mg IV or PO once daily plus SOC for up to 10 days or until discharge (n = 2,104)
  • SOC alone (n = 4,321)

Primary Endpoint:

  • All-cause mortality at 28 days

Participant Characteristics:

  • Mean age 66 years; 64% men
  • 56% had ≥1 comorbidity; 24% with diabetes
  • 89% with laboratory-confirmed SARS-CoV-2 infection
  • Median duration of DEX therapy: 7 days
  • At randomization: 16% received MV or ECMO, 60% required supplemental oxygen but not MV, 24% required no supplemental oxygen
  • Received RDV: <1% in each arm
  • Received tocilizumab or sarilumab: 2% in DEX arm vs. 3% in SOC arm

Primary Outcome:

  • Mortality at 28 days
    • All participants: 23% in DEX arm vs. 26% in SOC arm (age-adjusted rate ratio 0.83; 95% CI, 0.75–0.93; P < 0.001).
    • Participants who required MV or ECMO at randomization: 29% in DEX arm vs. 41% in SOC arm (rate ratio 0.64; 95% CI, 0.51–0.81).
    • Participants who required supplemental oxygen but not MV at randomization: 23% in DEX arm vs. 26% in SOC arm (rate ratio 0.82; 95% CI, 0.72–0.94).
    • Participants who did not require supplemental oxygen at randomization: 18% in DEX arm vs. 14% in SOC arm (rate ratio 1.19, 95% CI, 0.91–1.55).
Key Limitations:
  • Open-label study
  • Published data did not include results for key secondary endpoints (e.g., cause-specific mortality, need for renal replacement), AEs, and key subgroups (e.g., patients with comorbidities)
  • Participants who required supplemental oxygen (but not MV) had variable severity. It is unclear whether all patients in this group benefited from DEX or whether benefit is restricted to those requiring higher levels of supplemental oxygen
  • Patients >80 years were preferentially assigned to supplemental oxygen therapy (and not MV)
  • High mortality of this patient population may limit generalizability of results to populations with a lower baseline mortality

Interpretation:

  • In hospitalized patients with severe COVID-19 who required supplemental oxygen, DEX reduced mortality at 28 days, with greatest benefit in those with MV at randomization.
  • No survival benefit of DEX in patients who did not require supplemental oxygen at baseline.
CoDEX: Open-Label RCT of Dexamethasone in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19 in Brazil2
Key Inclusion Criteria:
  • Confirmed or suspected COVID-19
  • Received MV within 48 hours of meeting criteria for moderate to severe ARDS (PaO2/FiO2 ≤200 mm Hg)

Key Exclusion Criteria:

  • Immunosuppressive drugs in past 21 days
  • Expected death within 24 hours

Interventions:

  • DEX 20 mg IV daily for 5 days, then DEX 10 mg IV daily for 5 days or until ICU discharge (n = 151)
  • SOC alone (n = 148)

Primary Endpoint:

  • Days alive and free from MV by Day 28

Key Secondary Endpoints:

  • All-cause mortality at Day 28
  • ICU-free days by Day 28
  • Duration of MV by Day 28
  • Score on 6-point ordinal scale at Day 15
  • SOFA score at 7 days

Participant Characteristics:

  • Mean age: 60 years in DEX arm vs. 63 years in SOC arm
  • Women: 40% in DEX arm vs. 35% in SOC arm
  • Obesity: 31% in DEX arm vs. 24% in SOC arm; DM: 38% in DEX arm vs. 47% in SOC arm
  • Vasopressor use: 66% in DEX arm vs. 68% in SOC arm; mean PaO2/FiO2: 131 mm Hg in DEX arm vs. 133 mm Hg in SOC arm
  • Median duration of DEX therapy: 10 days
  • None received RDV or tocilizumab
  • 35% in SOC arm received corticosteroids for indications such as bronchospasm or septic shock

Primary Outcome:

  • Mean number of days alive and free from MV by Day 28: 7 days in DEX arm vs. 4 days in SOC arm (P = 0.04).

Secondary Outcomes:

  • No differences in arms for Day 28 all-cause mortality (56.3% vs. 61.5%), ICU-free days, and duration of MV, or for Day 15 score on 6-point ordinal scale.
  • Mean SOFA score at 7 days: 6.1 in DEX arm vs. 7.5 in SOC arm (P = 0.004).

Other Outcome:

  • Post hoc analysis of probability of death or MV by Day 15: 68% in DEX arm vs. 80% in SOC arm (OR 0.46; P = 0.01).
Key Limitations:
  • Open-label study
  • Underpowered; enrollment stopped after release of data from the RECOVERY trial
  • Patients discharged before 28 days were not followed for rehospitalization or mortality
  • High mortality in this study may limit generalizability to populations with a lower baseline mortality
  • More than one-third of those randomized to SOC also received corticosteroids

Interpretation:

  • Compared with SOC alone, DEX increased the number of days alive and free of MV over 28 days in patients with COVID-19 and moderate to severe ARDS.
COVID STEROID 2: Multinational Blinded RCT of Dexamethasone 12 mg Versus 6 mg in Adults With COVID-19 and Severe Hypoxemia3
Key Inclusion Criteria:
  • Confirmed SARS-CoV-2 infection
  • Requiring oxygen ≥10 L/min, NIV, CPAP, or MV

Key Exclusion Criteria:

  • Treated with DEX >6 mg (or equivalent)
  • Treated with corticosteroid ≥5 days
  • Invasive fungal infection
  • Active TB

Interventions:

  • DEX 12 mg IV once daily for up to 10 days (n = 503)
  • DEX 6 mg IV once daily for up to 10 days (n = 497)

Primary Endpoint:

  • Days alive without life support (MV, circulatory support, or kidney replacement therapy) at 28 days

Key Secondary Endpoints:

  • Days alive without life support at 90 days
  • Days alive and out of hospital at 90 days
  • Mortality at 90 days
  • Mortality at 28 days
  • SAEs at 28 days

Participant Characteristics:

  • Median age 65 years; 31% women
  • DM: 27% in 12 mg arm vs. 34% in 6 mg arm
  • Median onset of symptoms to hospitalization: 7 days
  • ICU care: 78% in 12 mg arm vs. 81% in 6 mg arm
  • Oxygen requirements: 54% on oxygen via nasal cannula or face mask (median flow rate 23 L/min); 25% via NIV; 21% via MV
  • 63% received RDV; 12% received IL-6 inhibitors or JAK inhibitors
  • Median duration of DEX treatment: 7 days in both arms

Primary Outcome:

  • Median days alive without life support: 22 days in 12 mg arm vs. 20 days in 6 mg arm (adjusted mean difference 1.3 days; 95% CI, 0.0–2.6; P = 0.07).

Secondary Outcomes:

  • At 90 days:
    • Median days alive without life support: 84 days in 12 mg arm vs. 80 days in 6 mg arm.
    • Median days alive and out of hospital: 62 days in 12 mg arm vs. 48 days in 6 mg arm.
    • Mortality: 32% in 12 mg arm vs. 38% in 6 mg arm (adjusted relative risk 0.87; 99% CI, 0.70–1.07).
  • Mortality at 28 days: 27% in 12 mg arm vs. 32% in 6 mg arm (adjusted relative risk 0.86; 99% CI, 0.68–1.08).
  • SAEs, including septic shock and invasive fungal infections: 11% in 12 mg arm vs. 13% in 6 mg arm (adjusted relative risk 0.83; 99% CI, 0.54–1.29).
Key Limitation:
  • The randomized intervention was <10 days in some patients because the trial allowed up to 5 days of DEX before enrollment

Interpretation:

  • Among patients with COVID-19 and severe hypoxemia, DEX 12 mg once daily did not result in more days alive without life support at 28 days than DEX 6 mg once daily.
CAPE COVID: Double-Blind RCT of Hydrocortisone Among Critically Ill Patients With COVID-19 in France4
Key Inclusion Criteria:
  • Confirmed SARS-CoV-2 infection or radiographically suspected COVID-19 with ≥1 of the following:
    • MV with PEEP ≥5 cm H2O
    • PaO2/FiO2 <300 mm Hg and FiO2 ≥50% on HFNC
    • PaO2/FiO2 <300 mm Hg on reservoir mask oxygen
    • Pulmonary severity index >130

Key Exclusion Criteria:

  • Septic shock
  • Do-not-intubate orders

Interventions:

  • Continuous infusion of hydrocortisone 200 mg/day for 7 days, then 100 mg/day for 4 days, then 50 mg/day for 3 days; if improvement by Day 4, then 200 mg/day for 4 days, then 100 mg/day for 2 days, then 50 mg/day for 2 days (n = 76)
  • Placebo (n = 73)

Primary Endpoint:

  • Treatment failure (death or dependency on MV or high-flow oxygen) by Day 21

Key Secondary Endpoints:

  • Need for MV, prone positioning, ECMO, inhaled nitric oxide
  • Nosocomial infection by Day 28
  • Clinical status on Day 21

Participant Characteristics:

  • Mean age 62 years; 70% men; median BMI 28
  • 96% with confirmed SARS-CoV-2 infection
  • Median symptom duration: 9–10 days
  • Required MV: 81% at baseline
  • Received vasopressors: 24% in hydrocortisone arm vs. 18% in placebo arm
  • Received RDV and tocilizumab: <3%
  • Median duration of treatment with study drug: 11 days in hydrocortisone arm vs. 13 days in placebo arm (P = 0.25)

Primary Outcomes:

  • Treatment failure by Day 21: 42% in hydrocortisone arm vs. 51% in placebo arm (P = 0.29).

Secondary Outcomes:

  • No difference in need for intubation or prone positioning (too few patients received ECMO or inhaled nitric oxide for comparisons).
  • Among patients who did not require MV at baseline, 50% in hydrocortisone arm vs. 75% in placebo arm required subsequent MV.
  • No difference in proportion with nosocomial infection by Day 28
  • Clinical status on Day 21: no difference in arms, but 15% deaths in hydrocortisone arm vs. 27% deaths in placebo arm (P = 0.06).
  • Discharged from ICU by Day 21: 57% in hydrocortisone arm vs. 44% in placebo arm; 23% in both arms still required MV.
Key Limitations:
  • Underpowered; enrollment stopped after release of data from the RECOVERY trial
  • Limited information about comorbidities

Interpretation:

  • Hydrocortisone did not reduce treatment failure at Day 21 in patients with COVID-19 and acute respiratory failure, although early termination limited power to detect difference between study arms.
REMAP-CAP: Randomized, Open-Label, Adaptive Trial of Hydrocortisone in Patients With Severe COVID-195
Key Inclusion Criteria:
  • Presumed or confirmed SARS-CoV-2 infection
  • ICU admission for respiratory support

Key Exclusion Criteria:

  • Presumed imminent death
  • Systemic corticosteroid use
  • >36 hours since ICU admission

Interventions:

  • Hydrocortisone 50 mg IV 4 times daily for 7 days (n = 137)
  • Septic shock-based hydrocortisone 50 mg IV 4 times daily for duration of shock (n = 146)
  • No hydrocortisone (n = 101)

Primary Endpoint:

  • Days free of respiratory and cardiovascular support up to Day 21

Key Secondary Endpoint:

  • In-hospital mortality

Participant Characteristics:

  • Mean age 60 years; 71% men
  • Mean BMI 29.7–30.9
  • 50% to 64% required MV

Primary Outcomes:

  • No difference in organ support–free days at Day 21 (median 0 days in each group).
  • Median adjusted ORs for primary outcome for hydrocortisone arms compared to no hydrocortisone arm:
    • OR 1.43 (95% CrI, 0.91–2.27) with 93% Bayesian probability of superiority for fixed-dose hydrocortisone arm.
    • OR 1.22 (95% CrI, 0.76–1.94) with 80% Bayesian probability of superiority for septic shock-based hydrocortisone arm.

Key Secondary Outcome:

  • No differences in mortality: 30% in fixed-dose hydrocortisone arm, 36% in septic shock-based hydrocortisone arm, 33% in no hydrocortisone arm.
Key Limitations:
  • Open-label study
  • Early termination following release of RECOVERY trial results

Interpretation:

  • Hydrocortisone did not increase support-free days in either the fixed-dose or the shock-dependent group, although early termination limited power to detect differences between study arms.
Single-Blind RCT of Methylprednisolone in Hospitalized Patients With COVID-19 Pneumonia in China6
Key Inclusion Criteria:
  • Laboratory-confirmed SARS-CoV-2 infection
  • Chest CT-confirmed pneumonia
  • Hospitalized on general ward

Key Exclusion Criteria:

  • Severe immunosuppression
  • Corticosteroid use for other diseases

Interventions:

  • Methylprednisolone 1 mg/kg/day IV for 7 days (n = 43)
  • Saline (n = 43)
Primary Endpoint:
  • Clinical deterioration at 14 days
Key Secondary Endpoints:
  • Clinical cure at 14 days
  • Time to clinical cure
  • ICU admission
  • In-hospital mortality
  • Days hospitalized

Participant Characteristics:

  • Mean age 56 years; 48% men
  • Median 8 days from symptom onset to randomization
  • At randomization, 71% received oxygen via nasal cannula

Primary Outcome:

  • Clinical deterioration at 14 days: 5% in each arm (OR 1.0; 95% CI, 0.134–7.442; P = 1.00).

Secondary Outcomes:

  • No difference (all P > 0.05) between methylprednisolone arm and saline arm for:
    • Clinical cure at 14 days: 51% vs. 58%
    • Time to clinical cure: 14 days vs. 12 days
    • ICU admission: 5% each
    • In-hospital mortality: 0% vs. 2%
    • Days hospitalized: 17 days vs. 13 days
Key Limitations:
  • Small sample size
  • Terminated early because of decreasing incidence of COVID-19 pneumonia at study sites

Interpretation:

  • The incidence of clinical deterioration did not differ between the methylprednisolone and control arms.

References

  1. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384(8):693-704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32678530.
  2. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324(13):1307-1316. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876695.
  3. COVID Steroid Trial Group, Munch MW, Myatra SN, et al. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. JAMA. 2021;326(18):1807-1817. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34673895.
  4. Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1298-1306. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876689.
  5. Angus DC, Derde L, Al-Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020;324(13):1317-1329. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876697.
  6. Tang X, Feng YM, Ni JX, et al. Early use of corticosteroid may prolong SARS-CoV-2 shedding in non-intensive care unit patients with COVID-19 pneumonia: a multicenter, single-blind, randomized control trial. Respiration. 2021;100(2):116-126. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33486496.