By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: Baricitinib significantly reduced mortality in patients with COVID-19 receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO).

SOURCE: Ely EW, Ramanan AV, Kartman CE, et al. Baricitinib plus standard of care for hospitalized adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: Results of a randomized, placebo-controlled trial. Abstract LB3. IDWeek 2021.

In the large adaptive ACTT-2 trial, baricitinib (a selective JAK-1 inhibitor) plus remdesivir was superior to remdesivir alone in the treatment of hospitalized patients with COVID-19, approximately one-fifth of whom received glucocorticoids.1 However, although improved outcomes were demonstrated in patients receiving high-flow oxygen or noninvasive ventilation, no such benefit occurred in those receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO) at the time of enrollment. The rate ratio for recovery in that group was only 1.08 (95% confidence interval [CI], 0.59 to 1.97).

In COV-BARRIER, another large multicenter trial, baricitinib failed to achieve a statistically significant improvement relative to placebo in meeting the primary endpoint, which was the proportion progressing to noninvasive ventilation, invasive mechanical ventilation, or death by 28 days.2 Although failing to improve the composite endpoint, the 28-day mortality was significantly lower in baricitinib recipients, with a difference of 4.8% (95% CI, -8.0% to -1.9%) and a hazard ratio (HR) of 0.56 (95% CI, 0.41 to 0.77). Nineteen percent of patients in the study received remdesivir and 79% received corticosteroids.

Ely et al presented the results of a substudy of COV-BARRIER at IDWeek, examining outcomes in just the patients who were receiving invasive mechanical ventilation or ECMO at study entry. When compared to placebo, baricitinib administration significantly reduced all-cause 28-day mortality (39.2% vs. 58.0%, respectively; HR = 0.54; 95% CI, 0.31, 0.96; P = 0.030; relative risk [RR] = 0.68; 95% CI, 0.45, 1.02) in these patients. The mortality benefit persisted to day 60 (45.1% vs. 62.0%; HR = 0.56; 95% CI, 0.33, 0.97; P = 0.027; RR = 0.73; 95% CI, 0.50, 1.06), and the number needed to treat to prevent one death was six.

COMMENTARY  

Baricitinib inhibits the JAK1/JAK2 tyrosine kinase-associated intracellular signaling pathways of several pro-inflammatory cytokines, including interleukin-2, interleukin-6, interleukin-10, interferon gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, it is reported to impair SARS-CoV-2 cell entry.

Perhaps somehow anticipating the results of the substudy of COV-BARRIER, the Food and Drug Administration, on Nov. 19, 2020, issued an Emergency Use Authorization for the use of baricitinib in combination with remdesivir in hospitalized adults and children 2 years of age and older with COVID-19 who require supplemental oxygen, invasive mechanical ventilation (IMV), or ECMO.

The current National Institutes of Health guideline (as of Oct. 9, 2021) includes a recommendation to give baricitinib or tocilizumab, in addition to dexamethasone with or without remdesivir, to recently hospitalized (“For example, within three days of hospital admission”) patients with rapidly increasing oxygen need (requiring high-flow oxygen or noninvasive ventilation) and signs of inflammation. For patients receiving IMV or ECMO, the guideline recommends dexamethasone and, for those within 24 hours of intensive care unit admission, the recommendation is to give tocilizumab (or sarilumab if tocilizumab is unavailable or infeasible), and it does not recommend baricitinib in this patient subset.3 Perhaps this recommendation will change when the data presented by Ely and colleagues is examined more fully.

REFERENCES

  1. Kalil AC, Patterson TF, Mehta AK, et al; ACTT-2 Study Group Members. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med 2021;384:795-807.
  2. Marconi VC, Ramanan AV, de Bono S, et al; COV-BARRIER Study Group. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): A randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med 2021:S2213-2600(21)00331-3. doi: 10.1016/S2213-2600(21)00331-3. [Online ahead of print]. Erratum in: Lancet Respir Med 2021;9:e102.
  3. National Institutes of Health. COVID-10 Treatment Guidelines. Clinical Management Summary. Updated Sept. 24, 2021. https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/clinical-management-summary/