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

Abstract

Background: Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19.

Methods: In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027.

Findings: Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups.

Interpretation: Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19.

Funding: Eli Lilly and Company.

Translations: For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Figure 1

Trial profile *159 deaths were reported by day 28; an additional three deaths occurred after the treatment period disposition but within 28 days.

Figure 2

Kaplan-Meier estimates of 28-day and 60-day all-cause mortality, and distribution of participants with each NIAID-OS score over time (A–F) 28-day all-cause mortality in population 1, the overall population (A); population 2, comprising participants who, at baseline, required oxygen supplementation and were not receiving dexamethasone or other systemic corticosteroids for the primary study condition (B); populations with baseline NIAID-OS scores of 5 (C) or 6 (D); and populations with (E) and without (F) baseline systemic corticosteroid use. The number at risk at day 27 represents the number of participants with available data at day 28. (G) 60-day all-cause mortality in population 1. The number at risk and number censored before day 28 differ slightly between panels A and G because the day 60 database contained further information on eight participants who were censored at the day 28 database lock but were known to be alive at the day 60 database lock. The number at risk at day 59 represents the number of participants with available data at day 60. For time-to-event endpoints, the p value for baricitinib versus placebo was calculated using an unstratified log-rank test, and HRs and 95% CIs were calculated using a Cox proportional hazards model. The treatment effect was adjusted by all baseline randomisation factors, except when redundant (ie, for baseline corticosteroid use in population 2). (H) Distribution of participants in each NIAID-OS category over time, among patients in the intention-to-treat population with available baseline NIAID-OS scores and at least one post-baseline NIAID-OS score, using last observation carried forward. An NIAID-OS score of 5 represents patients who are hospitalised and require supplemental oxygen, and a score of 6 represents patients who are hospitalised and receiving oxygen support via high-flow oxygen devices or non-invasive ventilation. HR=hazard ratio. NIAID-OS=National Institute of Allergy and Infectious Disease Ordinal Scale.

Figure 3

28-day all-cause mortality by subgroup HRs and 95% CIs were calculated with a Cox proportional hazards model. The treatment effect was adjusted by all baseline randomisation factors, except when redundant (eg, for age group [<65 or ≥65 years] in the age subgroup analyses). HR=hazard ratio. NIAID-OS=National Institute of Allergy and Infectious Disease Ordinal Scale. *Participants who, at baseline, required oxygen supplementation and were not receiving dexamethasone or other systemic corticosteroids for the primary study condition.