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

• Authors: Vincent Marconi, Emory University; Athimalaipet V Ramanan, University of Bristol; Stephanie de Bono, Eli Lilly and Company; Cynthia E Kartman, Eli Lilly and Company; Venkatesh Krishnan, Eli Lilly and Company; Ran Liao, Eli Lilly and Company; Maria Lucia B Piruzeli, Eli Lilly and Company; Jason D Goldman, Swedish Medical Center; Jorge Alatorre-Alexander, Instituto Nacional de Enfermedades Respiratorias; Rita DC Pellegrini, Pesquisare; Vicente Estrada, Universidad Complutense; Mousumi Som, Oklahoma State University; Anabela Cardoso, Eli Lilly and Company; Sujatro Chakladar, Eli Lilly and Company; Brenda Crowe, Eli Lilly and Company; Paulo Reis, Eli Lilly and Company; Xin Zhang, Eli Lilly and Company; David H Adams, Eli Lilly and Company; Wesley E Ely, Vanderbilt University
• Journal Title: LANCET RESPIRATORY MEDICINE
• Volume: Volume 9, Number 12
• Publisher: ELSEVIER SCI LTD | 2021-11-30, Pages 1407-1418
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/S2213-2600(21)00331-3
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Critical Care Medicine; Respiratory System; General & Internal Medicine; PNEUMONIA; THERAPY

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.