Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial

Abstract

Background: The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in studies of hospitalised adults with COVID-19. COV-BARRIER (NCT04421027) was a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in critically ill hospitalised adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation.

Methods: This exploratory trial followed the study design of COV-BARRIER in a critically ill cohort not included in the main phase 3 trial. The study was conducted across 18 hospitals in Argentina, Brazil, Mexico, and the USA. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection on baseline invasive mechanical ventilation or extracorporeal membrane oxygenation were randomly assigned (1:1) to baricitinib (4 mg) or placebo once daily for up to 14 days in combination with standard of care. Participants, study staff, and investigators were masked to study group assignment. Prespecified endpoints included all-cause mortality through days 28 and 60, number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. The efficacy analysis was done in the intention-to-treat population and the safety analysis was done in the safety population. This trial is registered with ClinicalTrials.gov, NCT04421027.

Findings: Between Dec 23, 2020, and April 10, 2021, 101 participants were enrolled into the exploratory trial and assigned to baricitinib (n=51) or placebo (n=50) plus standard of care. Standard of care included baseline systemic corticosteroid use in 87 (86%) participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared with placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31-0·96]; p=0·030; 46% relative reduction; absolute risk reduction 19%). A significant reduction in 60-day mortality was also observed in the baricitinib group compared with the placebo group (23 [45%] events vs 31 [62%]; HR 0·56 [95% CI 0·33-0·97]; p=0·027; 44% relative reduction; absolute risk reduction 17%). In every six baricitinib-treated participants, one additional death was prevented compared with placebo at days 28 and 60. The number of ventilator-free days did not differ significantly between treatment groups (mean 8·1 days [SD 10·2] in the baricitinib group vs 5·5 days [8·4] in the placebo group; p=0·21). The mean duration of hospitalisation in baricitinib-treated participants was not significantly shorter than in placebo-treated participants (23·7 days [SD 7·1] vs 26·1 days [3·9]; p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment groups.

Interpretation: In critically ill hospitalised patients with COVID-19 who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) reduced mortality, which is consistent with the mortality reduction observed in less severely ill patients in the hospitalised primary COV-BARRIER study population. However, this was an exploratory trial with a relatively small sample size; therefore, further phase 3 trials are needed to confirm these findings.

Funding: Eli Lilly and Company.

Conflict of interest statement

Declaration of interests EWE reports research grants from the US Centers for Disease Control and Prevention (CDC), NIH, and Veterans Affairs; and has served as an unpaid consultant for Eli Lilly and Company. AVR reports research grants from Eli Lilly and Company; and has served as a speaker or consultant for AbbVie, Eli Lilly and Company, Novartis, Pfizer, Roche, Sobi, and Union Chimique Belge. CEK, SdB, RL, MLBP, and SC are employees and shareholders of Eli Lilly and Company. JDG reports research support from Eli Lilly and Company, Regeneron Pharmaceuticals, and Gilead Sciences; grants from NIH, Biomedical Advanced Research and Development Authority (administered by Merck), and Eurofins Viracor; and has served as a speaker or consultant for Eli Lilly and Company, Gilead Sciences, and Mylan Pharmaceuticals. JFKS reports research grants from Eli Lilly and Company; and has served as a speaker or consultant for Eli Lilly and Company, Amgen, Novartis, Janssen, and NovoNordisk.​ VCM reports research grants from the CDC, Gilead Sciences, NIH, Veterans Affairs, and ViiV Healthcare; honoraria from Eli Lilly and Company; has served as an advisory board member for Eli Lilly and Company and Novartis; and has participated as a study section chair for the NIH.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Trial profile One participant in the baricitinib plus standard of care group did not have a recorded treatment period disposition form, so the treatment period disposition was missing. *Four participants discontinued from the trial after transfer to another hospital; they were included in the intention-to-treat population, with all available information used to inform the mortality and safety analyses. Specifically, three participants died after transfer and time of death was used in the mortality analysis. One participant was alive at follow-up and censored at the last available visit.

Figure 2

Kaplan-Meier estimates of all-cause mortality by day 28 and by day 60 (A) 28-day all-cause mortality. (B) 60-day all-cause mortality. All-cause mortality includes deaths potentially related with COVID-19 and deaths attributed to adverse events. The numbers at risk at days 27 and 59 represent the numbers of participants with available data at days 28 and 60, respectively. The data in parentheses below the curve represent the numbers of deaths that occurred during the interval until the next timepoint. HRs and 95% CIs were calculated using a Cox proportional hazard regression model adjusted for treatment group, age (vs ≥65 years), and geographical region (USA vs the rest of the world); unstratified. p values were calculated from an unstratified log-rank test. HR=hazard ratio.