COVID-19 Management Evidence

Steroid therapy

PRINCIPLE Study

• Adults with COVID treated with inhaled budesonide (800mcg twice daily) for up to 14 days
• Inclusion criteria for those at risk of progression:
  • Diabetes (not treated with insulin)
  • Heart disease or hypertension
  • Asthma or lung disease
  • Immunosuppression
  • Mild hepatic impairment
  • Stroke or other neurological issue
• Decreases the requirement of supplemental oxygen if taken within 14 days of onset of symptoms

RECOVERY Study (June 2020)

• 2104 patients randomised to dexamethasone 6mg daily for 10 days vs. 4321 patients who received usual care
• Primary outcome: 28 day mortality was significantly reduced in dexamethasone group (21.6 vs. 24.6%)
• Secondary outcomes:
  • Dexamethasone reduced 28-day mortality in mechanically ventilated patients, patients receiving oxygen; reduced hospital LOS by 1 day and reduced rates of ventilation
• NNT = 8 for reducing mortality in mechanically ventilated patients
• NNT= 25 for reducing mortality in patients requiring oxygen
• Not helpful for patients not requiring mechanical ventilation or oxygen therapy
• More likely to be helpful if started >7 days from onset of symptoms

REMAP-CAP (2020)

• Hydrocortisone in severe COVID-19 patients (HFNC >30L and FiO2 >0.4, NIV or invasive ventilation or cardiovascular support
• 403 enrolled to corticosteroid arm
  • 143 fixed dose (50mg q6h for 7 days)
  • 152 shock dose (50mg q6h whilst in shock up to 28 days) in those with cardiovascular shock
  • 108 no hydrocortisone
• Primary outcome
  • No significant difference in respiratory and cardiovascular support-free days
  • Did provide high probability of superiority (Bayesian approach) of corticosteroid use in organ support-free days within 21 days
• Also reported large reduction in progression to invasive ventilation, ECMO or death with the hydrocortisone regimes above

Antivirals

Remdesivir

ACTT-1

• Tested Remdesivir in hospitalised patients with SARS-Cov-2 compared to placebo
• Active metabolite of Remdesivir interferes with the action of viral RNA-dependent RNA polymerase thereby reducing viral RNA production
• Participants had to require supplemental O2, mechanical ventilation or ECMO
• 1059 patients studied
• Primary outcome
  • Significantly shorter time to recovery with Remdesivir: 11 days vs. 15 days
  • No difference in those on MV or ECMO at time of randomisation
• No significant difference in mortality
• Odds of improvement in ordinal scale score measured at day 15 were higher in Remdesivir group

Gottlieb et al.

• Double-blind RCT of 562 patients showed IV remdesivir use within 7 days of symptom onset in non-hospitalised adults with at least one risk factor for disease progression (see below) resulted in an 87% lower rate of hospitalisation or death at 28 days
• Risk factors for progression
  • >= 60 years
  • Obesity
  • HTN
  • Cardiovascular disease
  • Cerebrovascular disease
  • DM
  • Obesity
  • Immunocompromise
  • Chronic liver disease
  • Chronic lung disease
  • Cancer
  • Sickle cell disease
  • Chronic mild or moderate kidney disease

Molnupiravir

Bernal et al.

• Oral, small-molecule prodrug active against SARS-COV-2
• Phase 3, double-blind, placebo-controlled RCT of 1433 patients within 5 days of symptoms in non-hospitalised unvaccinated patients with at least one risk factor for progression
• Hospitalisation or death from any cause reduced to 7.3% vs. 14.1%

Immunomodulators

Tocilizumab

BACC trial (December 2020)

• Studied the benefit of Tocilizumab in hospitalised patients with severe ARDS due to SARS-Cov-2
• Early trials in Chinese patients showed high circulating levels of IL-6 associated with progression to mechanical ventilation and death
• Tocilizumab is an IL-6 receptor blocker monoclonal antibody
• This was a double-blinded randomised control trial of 243 patients across 7 hospitals in Boston, USA
• Inclusion criteria
  • Age 19-85
  • Confirmed SARS-Cov-2
  • Two of:
    • Fever, pulmonary infiltrate, need for supplemental O2
  • AND one of:
    • CRP >50, ferritin >500ng/mL, D-dimer >1000ng/mL or LDH >250u/L
• Exclusion criteria
  • Supplemental O2 >10L/min
  • Recent biologic agent or immunosuppressive therapy
  • Diverticulitis

• Some patients received remdesivir and no patients received hydrocortisone
• Primary outcome: No significant difference in intubation or death by day 28
• Conclusion is that in this moderately unwell cohort, Tocilizumab was not beneficial

REMAP-CAP IL-6

• Included patients in ICU receiving mechanical ventilation, HFNP >30L/min and FiO2 >0.4 or cardiovascular support
• Compared IL-6 inhibitors with placebo in a Bayesian design with multiple intervention cohorts
• Could repeat dose of Tocilizumab at 12-24 hours at clinician discretion
• Primary outcomes
  • Significantly increased number of organ support-free days (OR 1.64)
  • Significantly reduced hospital mortality (OR 1.64)
• Secondary outcomes
  • Significantly improved 90-day survival, time to ICU discharge and progression to invasive ventilation, ECMO or death
  • No significant difference in adverse effects

Baricitinib

COV-BARRIER

• Tested Baricitinib (a JAK 1/2 inhibitor) in hospitalised patients with SARS-Cov-2 pneumonia
• ACTT-2 showed reduction in time to recovery in combination with Remdesivir vs. Remdesivir alone
• Patients included if hospitalised but NOT mechanically ventilated (and later in study had to require O2 therapy)
• 12 countries across the world
• No significant difference in composite endpoint of progression to NIV/HFNP/MV/ECMO/Death by day 28
• A significant reduction was seen in all cause mortality (NNT = 20 at day 28)
• Seems to be more beneficial in those who were sicker at baseline (needing O2 supplementation at randomisation)

ACTT-2

• Baricitinib plus Remdesivir vs. Remdesivir alone in hospitalised patients with COVID-19
• 1033 patients were randomised
• Baricitinib group showed signficantly faster recovery (7 days vs. 8 days) and 30% higher odds of improvement in clinical status at day 15
• Patients on HFNP or NIV at randomisation had a time to recovery of 10 days vs. 15 days in control group
• 28 day mortality was 5.1% in combination cohort vs. 7.8% in control group

Carsirivimab and Imdevimab (REGEN-COV)

RECOVERY REGEN-COV

• Addition of carsirivimab and imdevimab monoclonal antibodies (REGEN-COV) to standard care
• These are non-competitive monoclonal antibodies that bind to the receptor binding domain of the spike glycoprotein on SARS-Cov-2, blocking viral entry into host cells
• Two antibodies were used that bind to non-overlapping epitopes to minimise the risk of resistance
• 127 UK hospitals involved
• Primary outcome of 28 day mortality was significantly reduced in REGEN-COV group (24 vs. 30%; NNT 19) in the seronegative at baseline cohort
  • No significant difference if patients seropositive at baseline were included
• In seronegative patients
  • Significantly reduced progression to NIV or MV
  • No significant difference in progression to MV alone
  • Significantly greater proportion discharged alive from hospital within 28 days
• Benefits lost in seropositive patients at baseline

Sotrovimab

COMET-ICE

• Sotrovimab use in non-vaccinated adults not requiring oxygen with risk factors for progression:
  • Diabetes
  • Obesity
  • CKD
  • NYHA II or higher
  • COAD
  • Moderate to severe asthma
  • Age >=55
• Decreased the risk of hospitalisation if taken within 5 days of onset

Sarilumab

• Patients that require high-flow oxygen, non-invasive ventilation or invasive ventilation have a reduced risk of death
• REMAP-CAP
• Lescure et al. Lancet Resp medicine
• Sivapalasingam et al. medRxiv 2021

Convalescent Plasma

PlasmAr

• In patients with severe pneumonia due to SARS-Cov-2 no benefit shown with respect to mortality or other clinical outcomes at day 30

NIV

Recovery-RS

• Compared NIV, HFNP or conventional oxygen therapy in reducing progression to intubation or death in hospitalised patients with pneumonia from SARS-Cov-2
• 1277 patients randomised to CPAP vs. HFNP vs. COT
• Mean 9.5cmH20 CPAP, 50L/min HFNP
• Progression to intubation was at discretion of treating clinicians
• Primary outcome
  • Combined endpoint of intubation or death within 30 days was significantly reduced in CPAP group (NNT = 12) but not in HFNP group
• Secondary outcomes
  • ICU admission significantly less likely in CPAP group
  • Time to intubation longer in CPAP group (2.2 days vs. 1.0 days)
  • NO significant difference in duration of MV, ICU LOS or hospital LOS
  • Haemodynamic instability far more common in CPAP group

Chemoprophylaxis

REGEN-COV (O’Brien et al. NEJM 2021)

• Prophylactic casirivimab plus imdevimab reduces risk of symptomatic and asymptomatic COVID-19 infection in seronegative household contacts if provided within 4 days of exposure
• If serology not immediately available, can provide to those that are PCR-negative and considered unlikely to have had COVID before
• 600mg of each SC in trial
• Vaccinated individuals were excluded from this trial and it is not known if chemoprophylaxis is beneficial (or harmful) in this cohort
• This trial was performed prior to the Delta outbreak

No evidence for hydroxychloroquine

Proning

PRON-COVID

• Prone positioning previously shown to improve oxygenation and mortality in non-COVID ARDS
• Single-centre, prospective feasibility study in Italy of patients requiring supplemental oxygen or NIV
• Patients were encouraged to maintain prone positioning for at least 3 hours
• Patients could maintain prone positioning for up to 8 hours if desired
• Primary outcome of P/F ratio before and 1hr after proning
• 57 patients total enrolled
• Prone positioning was feasible (maintained for at least 3 hours) in 84% of patients

PROFLO

• Multicentre randomised trial comparing prone positioning targeting 16 hours per day or standard care
• Primary endpoint was intubation within 30 days
• 75 patients randomised
• Median hours prone per day was 3.4 in control group vs. 9 in prone group
• No change in rate of intubation within 30 days

Erhmann et al. Lancet Resp Med

• Meta-trial of 6 randomised trials of prone positioning for patients on HFNP
• Hazard ratio for intubation was 0.75 for prone positioning within 28 days of enrolment
• Rates of adverse events was low and similar between each group

Last Updated on December 29, 2021 by Andrew Crofton