Evidence before this study

We searched PubMed using the terms “COVID-19”, “SARS-CoV-2”, “treatment”, “baricitinib”, and “JAK inhibitor” for articles in English, published until April 31, 2020, regardless of article type. We considered previous and current clinical trials of investigational medications in COVID-19, as well as previous clinical trials of the Janus kinase (JAK)1 and JAK2 inhibitor baricitinib conducted before this study. At the time the COV-BARRIER study was designed, there were no approved therapies for the treatment of COVID-19. Management of COVID-19 was supportive, and few phase 3 randomised placebo-controlled studies had been completed. Some phase 2 and 3 data on the antimalarial hydroxychloroquine and protease inhibitor lopinavir–ritonavir were available, and trials investigating the use of the antiviral remdesivir were ongoing. Baricitinib was identified as a potential intervention for COVID-19 due to its mechanism of action as a JAK1 and JAK2 inhibitor, its known anticytokine properties, and a potential antiviral mechanism via targeting host proteins. Additionally, early case series evaluating the efficacy and safety of baricitinib in populations of hospitalised patients supported further evaluation of baricitinib as a potential treatment option for hospitalised patients with COVID-19. While the COV-BARRIER study was enrolling, ACTT-2, a phase 3 study evaluating baricitinib plus remdesivir, was completed and showed that baricitinib in combination with remdesivir improved time to recovery and other outcomes.

Added value of this study

This was the first phase 3 study to evaluate baricitinib in addition to the current standard of care, and included patients receiving antivirals, anticoagulants, and corticosteroids. After the earliest publication of the RECOVERY study in June, 2020, the treatment of hospitalised patients with COVID-19 changed with the adoption of dexamethasone as the standard of care. As a result of its design, COV-BARRIER became the first trial to evaluate the benefit and risk of baricitinib when added to the most current standard of care (dexamethasone) in these patients. This was a randomised, double-blind, placebo-controlled trial conducted globally in regions with high COVID-19 hospitalisation rates. The reduction in the composite primary endpoint of progression to non-invasive ventilation, high-flow oxygen, invasive mechanical ventilation, or death for baricitinib plus standard of care (including dexamethasone) compared with placebo plus standard of care was not statistically significant. However, analysis of a prespecified key secondary endpoint showed that treatment with baricitinib reduced 28-day all-cause mortality by 38·2% compared with placebo (HR 0·57 [95% CI 0·41–0·78], nominal p=0·0018), with one additional death prevented per 20 baricitinib-treated participants. The reduction of all-cause mortality with baricitinib was maintained up to day 60 in an exploratory analysis. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between the baricitinib and placebo groups.

Implications of all the available evidence

In this phase 3 trial, baricitinib administered in addition to standard of care (which predominantly included dexamethasone) did not reduce the incidence of a composite endpoint of disease progression, but showed a strong effect on reduction of mortality by 28 days, an effect which was maintained up to 60 days. In the ACTT-2 study, baricitinib further reduced time to recovery above the background use of remdesivir. Taken together, these findings suggest that baricitinib has synergistic effects with other standard-of-care treatment modalities, including remdesivir and dexamethasone. Based on all available evidence, baricitinib is a potentially effective oral treatment option to decrease mortality in hospitalised patients with COVID-19.