Corticosteroids

Randomized Control Trial

1.  RECOVERY Trial (Preprint only)
   The RECOVERY Trial is an open label randomized evaluation of COVID-19 therapy at 175 NHS hospitals in the UK.  The study compares usual care alone, lopinavir-ritonavir, hydroxychloroquine, azithromycin, and corticosteroids.  Eligible patients were also allocated simultaneously to no additional treatment vs. convalescent plasma. The steroid dosing was dexamethasone 6 mg/day or steroid equivalent for 10 days. Main outcomes were death, discharge, need for ventilation, and need for renal replacement therapy at 28 days. The total study has included over 11,500 patients. A total of 2104 patients were randomized to receive steroids and 4321 patients were randomized to usual care alone. A press release on 6/16/20 announced preliminary findings as follows: “Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75]; p=0.14).”
    
2. COVID STEROID 2 Trial
   COVID STEROID 2 is a multicenter, blinded randomized clinical trial conducted at 26 hospitals in Europe and India. This study compared dosing of IV dexamethasone 6mg/day to 12mg/day for up to 10 days in COVID-19 patients with severe hypoxemia (≥10L oxygen supplementation/minute independent of delivery system, use of non-invasive ventilation or continuous positive airway pressure for hypoxemia, or invasive mechanical ventilation). The primary outcome was number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days. Total of 982 patients were included, 491 patients in 12mg group and 480 patients in 6mg group. Findings using intention-to-treat analysis, median number of days alive without life support:12mg/d at 22 days and 6mg/d at 20.5 days with an adjusted mean difference of 1.3 days (95% CI, 0-2.6 days; p=0.07). No statistical significance was found, potentially a result of a type II error due to the small sample size.
   
   The authors did agree to pre-planned secondary Bayesian analysis of the results to address potential shortcomings. Clinically important differences were defined as an incidence rate ratio (IRR) >1 favors 12mg and mean difference (MD) >0 favors 12mg. For the primary outcome, IRR 1.09 (0.98-1.18) and MD 1.3 (-0.3 to 2.9 days).
   
   The differences defined in the analysis articulate lack of statistical significance does not equate to lack of clinical significance. Of note, both groups had received dexamethasone for a median of 1 day before enrollment. The use of concomitant anti-inflammatory agents (IL-6 receptor agonists, Janus kinase inhibitors) was only 12%.
3.  GLUCOCOVID Trial
   GLUCOCOVID partially randomized, open-label trial, multicentric trial in Spain demonstrated similar results to RECOVERY. This study compared SOC to SOC + methylprednisolone (40mg  bid x 3 days then 20mg BID X 3 days). Primary composite outcome was (all cause hospital mortality, escalation to ICU, progression to respiratory insufficiency requiring non-invasive ventilation). SoC (standard of care) vs MP (methylpred). (ITT) = intention to treat. 85 patient trial.
   • All patients composite outcome (ITT) - 48% (SoC) vs 34% (MP) - RR 0.7 (0.4-1.18)
   • < 72 yrs old (ITT) -  40% (SoC) vs 16% (MP) - RR 0.4 (0.14 - 1.14)
   • > 72 yrs old (ITT) - : 67% (SoC) vs 48% (MP) - RR 0.66 (0.66 - 1.11)
   • All patients (per protocol): 48% (MP) vs 24% (MP) - RR 0.5 (0.27 - 0.94)
   • 24% absolute reduction in primary endpoint with MP for all patients per protocol
   Limitations included lower sample size, open label.
    
4. HIGHLOWDEXA-COVID Trial
   The HIGHLOWDEXA-COVID trail is a randomized, open-label, controlled clinical trial. This study evaluated efficacy of high dose dexamethasone (20mg daily x 5 days, followed by 10mg daily x 5 more days) compared to low dose dexamethasone (6mg daily x 10days) in hospitalized COVID-19 pneumonia patients requiring oxygen to maintain saturation >92%. Primary outcome was clinical worsening within 11 days of randomization. Analysis was completed using intention-to-treat principles. Total of 200 patients enrolled.
   • 31.4% low dose group and 16.3% high dose group showed clinical worsening within 11 days (RR: 0.427; 95% CI 0.216-0.842; P=0.014)
   • No significant difference between groups in need of ICU admission, mechanical ventilation, in-hospital mortality, and in all-cause mortality at 28 days.
   • Adverse events and secondary infections were comparable
   Limitations: patient population (excluded patients requiring HFNC, NIMV, or MV) may exclude patients with comorbidities and high risk of mortality, sample size, study design (31.4% patients in low dose group received high dose following clinical worsening)

Observational SARS CoV-2

1.  Wang Y, Jiang W, He Q, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Sig Transduct Target Ther. 2020;5(57). https://doi.org/10.1038/s41392-020-0158-2 (human, retrospective observational study, effective)
2.  Zhou W., Liu Y., Tian D. et al. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia. Sig Transduct Target Ther. 2020;5(18). https://doi.org/10.1038/s41392-020-0127-9 (human, observational, effective)
3.  Russell, C. D., Millar, J. E. & Baillie, J. K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. https://doi.org/10.1016/s0140-6736(20)30317-2 (2020). (human, meta-analysis, not effective)
4.  Poston JT, Patel BK, Davis AM. Management of Critically Ill Adults With COVID-19. JAMA. Published online March 26, 2020. doi:10.1001/jama.2020.4914 (human, meta-analysis, not effective)
5.  Villar J, Confalonieri M, Pastores S, Meduri G.U. Rationale for Prolonged Corticosteroid Treatment in the Acute Respiratory Distress Syndrome Caused by Coronavirus Disease 2019. Crit Care Expl. 2020; 2:e0111 doi: 10.1097/CCE.0000000000000111 (human, meta analysis/literature review/opinion, effective)
6.  Henderson, L.A., Canna, S.W., Schulert, G.S., Volpi, S., Lee, P.Y., Kernan, K.F., Caricchio, R., Mahmud, S., Hazen, M.M., Halyabar, O., Hoyt, K.J., Han, J., Grom, A.A., Gattorno, M., Ravelli, A., de Benedetti, F., Behrens, E.M., Cron, R.Q. and Nigrovic, P.A. On the alert for cytokine storm: Immunopathology in COVID‐19. Arthritis Rheumatol. 2020; Accepted Author Manuscript. doi:10.1002/art.41285 (human, literature review, effective)

In vivo MERS CoV or SARS CoV-1

1. Meduri, G.U., Siemieniuk, R.A.C., Ness, R.A. et al. Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS. j intensive care 6, 53 (2018).
   An updated meta-analysis incorporating nine randomized trials (n = 816) investigating low-to-moderate dose prolonged glucocorticoid treatment in acute respiratory distress syndrome (ARDS) showed moderate-to-high quality evidence that glucocorticoid therapy is safe and:

   • Reduces time to endotracheal extubation, duration of hospitalization, and mortality (number to treat to save one life = 7)
   • Increases the number of days free from mechanical ventilation, intensive care unit stay, and hospitalization.

 In vivo SARS CoV-2

1. Villar J, Ferrando C, Martinez D et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Multicenter RCT of 17 ICUs in Spain, patients with moderate-severe ARDS. Lancet Respiratory Medicine. March 1, 2020. 8 (3). p267-276.

   • Primary outcome number of ventilator-free days at 28 days.
   • All analyses intention-to-treat.
   • Early administration of dexamethasone reduced duration of mechanical ventilation and overall mortality in patients with established moderate-to-severe ARDS.
      
2. Villar J, Belda J, Añón JM, et al. Evaluating the efficacy of dexamethasone in the treatment of patients with persistent acute respiratory distress syndrome: study protocol for a randomized controlled trial. Trials. 2016;17:342. Published 2016 Jul 22. doi:10.1186/s13063-016-1456-4

 In vitro SARS CoV-1/2 and MERS-CoV

1. A 2017 Cochrane review found: “Corticosteroid therapy reduced mortality and morbidity in adults with severe CAP; the number needed to treat for an additional beneficial outcome was 18 patients (95% CI 12 to 49) to prevent one death. Corticosteroid therapy reduced morbidity, but not mortality, for adults and children with non-severe CAP. Corticosteroid therapy was associated with more adverse events, especially hyperglycaemia, but the harms did not seem to outweigh the benefits.”
   
   Stern  A, Skalsky  K, Avni  T, Carrara  E, Leibovici  L, Paul  M. Corticosteroids for pneumonia. Cochrane Database of Systematic Reviews 2017, Issue 12. Art. No.: CD007720. DOI: 10.1002/14651858.CD007720.pub3.

Link to ClinicalTrials.gov for COVID-19 + corticosteroids search

1. CoDEX: The COVID-19 Dexamethasone (CoDEX) clinical trial was an open label randomized evaluation of dexamethasone treatment at 41 intensive care units in Brazil. The study compares standard of care treatment to two dosing schedules of dexamethasone. Patients enrolled if they had COVID-19 and moderate to severe ARDs. Steroid dosing was 20 mg of dexamethasone IV daiy for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge plus standard of care or standard of care alone. Primary outcome was ventilator-free days during the first 28 days. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores at 48 hours, 72 hours and 7 days. The study included 299 patients. A total of 151 patients received dexamethasone plus standard of care treatment and 148 received only standard of care treatment. The trial was terminated early on 06/25/2020 after the RECOVERY trial results were released due to loss of equipoise. Results showed patients in the dexamethasone group had a mean 6.6 ventilator-free days (95% confidence interval of 5.0-8.2) during the first 28 days vs 4.0 ventilator free days (95% confidence interval 2.9-5.4) in the standard of care group (p = 0.04). SOFA scores at 7 days showed a significant difference (p = 0.004) between the dexamethasone group with a score of 6.1 (95% confidence interval 5.5-6.7) vs 7.5 (95% confidence interval 6.9-8.1) in the standard of care group. The trial was halted early due to the release of the RECOVERY study results, with these results expanding their conclusion by showing that corticosteroids were effective even when the baseline mortality rate is high.
   1. Limitations:
      1. Open-label trial design
      2. Difference between groups of 2.26 days was lower than the effect size 3 days used in the sample size calculation
      3. Study underpowered for secondary outcomes (i.e. mortality)
          
2. REMAP-CAP (Randomized, embedded, multifactorial adaptive platform trial for Community-acquired pneumonia): The REMAP-CAP Trial is an open label randomized evaluation of COVID-19 therapy at 121 clinical sites in Australia, Canada, France, Ireland, the Netherlands, New Zealand, the UK and the US. The study compares standard of care, antiviral therapy, corticosteroids (hydrocortisone), targeted immune modulation, immunoglobulin and therapeutic anticoagulation. Only patients in the severe state were eligible for corticosteroids. The steroid dosing was fixed dose (IV hydrocortisone 50 mg every 6 hours for 7 days), shock-dependent dose (IV hydrocortisone 50 mg every 6 hours while in shock for up to 28 days) or standard of care with no corticosteroid. The primary outcome was respiratory and cardiovascular organ support-free days up to day 21. Secondary outcomes were in-hospital mortality, ICU and hospital length of stay, respiratory and/or cardiovascular organ support-free days, need for mechanical ventilation, ECMO or death, and the WHO ordinal scale assessed at day 14. The total study has included 614 patients. A total of 403 patients were randomized to receive steroids, 143 received fixed dose and 152 received shock-dependent dose with 108 receiving no steroids. The corticosteroid arm of the study was discontinued after the RECOVERY trial press release from 6/16/2020 due to loss of equipoise. Results demonstrated a median adjusted odds ratio and Bayesian probability of superiority of 1.43 (95% confidence interval 0.91-2.27) and 93% for fixed dose hydrocortisone and 1.22 (95% confidence interval 0.76-1.94) and 80% for shock-dependent hydrocortisone compared to treatment without steroids in patients with severe COVID-19. The trial was halted early due to the results of the RECOVERY study, so no treatment strategy met prespecified criteria for statistical superiority.
   1. Limitations:
      1. Open label design
      2. 15% of no corticosteroid group received systemic corticosteroids which could bias results toward a smaller effect size
      3. Terminated early, did not enroll enough patients for initially planned power
      4. Convenience sample of patients (non-consecutive enrollment)
      5. Fixed dose and shock dose groups appeared sicker to the no steroid group (more vasopressor support and higher APACHE II scores).
3. CAPE COVID: The Community-Acquired Pneumonia: Evaluation of Corticosteroids in Coronavirus Disease (CAPE COVID) trial was multicenter double-blind sequential trial conducted in French ICUs. The study compares low-dose hydrocortisone compared to placebo in critically ill patients with COVID-19 and acute respiratory failure. The dosing for hydrocortisone was 200 mg/d until day 7, then decreased to 100 mg/d for 4 days and 50 mg/d for 3 days for a total of 14 days. If a patient’s respiratory and general status had sufficiently improved by day 4, a short treatment course was used instead with 200 mg/d for 4 days, 100 mg/d for 2 days, and 50 mg/d for the last 2 days for a total of 8 days. Primary outcome was treatment failure on day 21. This was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen. Secondary outcomes included use of tracheal intubation, use of prone position, extracorporeal membrane oxygenation or inhaled nitric oxide, PaO2:FIO2 ratio recorded daily from day 1 to 7 and then on days 14 and 21, the proportion of patients with and the number of episodes of nosocomial infections recorded during the ICU stay. The study included 149 patients, with 76 receiving the hydrocortisone treatment and 73 receiving placebos. The trial was terminated prematurely after the RECOVERY study results were released. Results from this study showed no significant reduction in treatment failure at 21. Treatment failure on day 21 occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared to 37 of 73 (50.7%) in the placebo group (difference of proportions, -8.6% [95% confidence interval -24.9% to 7.7%], p = 0.29).
   1. Limitations: terminated after 149 patients, so underpowered to find significant differences in outcomes.