COV-BARRIER: Baricitinib in Hospitalized Adults with COVID19

Background: Outside of vaccines, effective pharmaceuticals for COVID19 continue to be evasive. Steroids have been a success (in patients who require supplemental O2) leading to additional studies investigating optimal drug and dose. Despite early excitement, we’ve seen high-quality studies demonstrate a lack of benefit for numerous drugs including colchicine, hydroxychloroquine, ritonavir etc. Some meds, like remdesivir and monoclonal antibodies (mAbs) targeting the spike protein of SARS-CoV2, are being widely used despite an absence of robust data supporting their use (Bamlanivimab, REGN-COV2, Remdesivir). 

Still, continued research and investigation is vital. One area research continues to focus on is the hyperactive inflammatory response that occurs as COVID19 progresses. Janus kinase-inhibitors (JAK-inhibitors) work by targeting and suppressing cytokine pathways. The ACTT-2 Trial published in the NEJM in December 2020 demonstrated a small decrease in time to recovery in patients treated with baricitinib (one day) that was barely statistically significant (PulmCrit 2020). Secondary outcomes (hypothesis generating) demonstrated improvements in progression of oxygen requirement and intubation as well as a non-significant trend towards decreased mortality. However, the majority of patients in this study did not receive steroids which became standard care in those with hypoxemia after the RECOVERY study. This raised questions about the utility of baricitinib when added to steroids. 

Paper: Marconi VC et al. Baricitinib plus standard of care for hospitalized adults with COVID-19. medRxiv 2021 Clinical Trials Registry

Clinical Question: Does the addition of baricitinib to usual care in adult hospitalized patients with COVID19 improve the rate of disease progression?

What They Did: Phase 3, multi-center, double-blind, randomized, placebo-controlled trial in 101 centers in 12 countries.

  • Protocol Change: After ACTT-2 results were published, COV-BARRIER changed their protocol to only include patients with baseline O2 requirement (ACTT-2 demonstrated that those not requiring O2 were not likely to progress)

Population: Adults > 18 years of age, hospitalized with SARS-CoV2 (confirmed by lab) with evidence of pneumonia or active, symptomatic COVID-19 and > 1 elevated inflammatory marker (CRP, D-dimer, LDH, Ferritin). 

Intervention: Baricitinib 4 mg daily (2 mg if GFR 30-60) for 14 days + standard care

Control: Placebo + standard care (SOC)


  • Primary: Progression to high-flow oxygen or non-invasive ventilation, invasive mechanical ventilation or ECMO or death at 28 days (composite primary outcome)
  • Key Secondary:
    • All-cause mortality
    • Proportion of patients with > 1 point improvement on NIAID-OS at 4, 7, 10 and 14 days
    • Number of ventilator-free days
    • Time to recovery


  • Outpatients
  • Already requiring invasive mechanical ventilation
  • Receiving immunosuppressants
  • Receiving convalescent plasma or IVIG
  • GFR < 30


  • Recruited 1525 patients
    • SOC N = 761
    • Baricitinib N = 764
    • 83.1% of patients completed follow up at 28-days
      • 62.6% of those not followed to 28 days were not followed due to death
  • All patients who were randomized were included in the intention-to-treat population
  • 79% of patients received steroids
  • VTE rates were similar between groups: 2.5% vs 2.7%


  • Asks a clinically important question
  • 1st multicenter, randomized, double-blind, placebo controlled trial to evaluate the potential benefit and safety of baricitinib plus SOC (including systemic corticosteroids and remdesivir)
  • Baseline demographics were well balanced between groups
  • Large, randomized trial
  • 6% of patients were lost to follow up (excludes those who died before 28 days)
  • Intention to treat analysis which better represents real clinical practice
  • Adapted study based on findings of ACTT-2


  • There’s no information in the publication about how patients were randomized or how blinding was achieved.
  • Composite endpoint where all parts are not clinically equivalent (death is worse than progression to non-invasive ventilation)
  • Funded by Eli Lilly the maker of baricitinib, which is why we may be seeing an emphasis on secondary outcomes.


  • Ultimately, this is a negative study as the primary endpoint was not statistically significantly different.
    • The secondary outcome showing a mortality benefit is interesting and hypothesis generating. 
      • ACTT-2 demonstrated a non-significant trend to benefit in mortality.
      • Subsequent studies should be performed with mortality as the primary outcome.
    • Despite mortality being a secondary outcome, the authors include it in their abstract and there’s a high likelihood that this will encourage clinicians to use it despite the absence of high-quality support.
  • Moderately ill group of COVID19 patients. This should guide clinicians who decide to use this drug. Baricitinib should not be given to outpatients or to those who are mechanically ventilated based on this data.
  • Adapted study based on findings of ACTT-2. In general, protocol changes are undesirable, in the middle of a pandemic it makes sense to build off of emerging clinical knowledge.
  • The mortality benefit appears to be more robust outside of Europe and the US. (See figure below). Does this reflect standard care differences? Differences in health care access? Differences due to capacity and surges? More granular data on this discrepancy would be useful.
  • Though baricitinib has prothrombotic effects, there was no difference in VTE rates.

Author Conclusion: While reduction of disease progression did not achieve statistical significance, treatment with baricitinib in addition to SOC (predominantly dexamethasone) significantly reduced mortality with a similar safety profile between groups of hospitalized COVID-19 participants “

Our Conclusion: Baricitinib did not show a benefit in terms of progression of COVID-19 disease in comparison to standard care. There is a signal for mortality benefit, but further studies are needed to verify this benefit prior to widespread use in moderately ill patients with COVID19.

Clinical Take Home Point: Baricitinib may, or may not, be a useful adjunct to standard care of patients with moderate COVID-19 but further study is needed before this becomes part of standard practice.


  1. Kalil AC et al. Baricitinib plus remdesivir for hospitalized adults with COVID-19. NEJM 2021 384(9): 795-807. PMID: 33306283

For More Thoughts on This Topic Checkout:

Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)

Cite this article as: Anand Swaminathan, "COV-BARRIER: Baricitinib in Hospitalized Adults with COVID19", REBEL EM blog, June 14, 2021. Available at:

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