Background: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, improved outcomes in a previous randomized controlled trial of hospitalized adults with COVID-19, in combination with remdesivir. Methods: In this phase 3, global, double-blind, randomized, placebo-controlled trial, 1525 hospitalized adults with COVID-19 receiving standard of care (SOC) were randomly assigned (1:1) to once-daily baricitinib 4-mg (N=764) or placebo (N=761) for up to 14 days. SOC included systemic corticosteroids in ~79% of participants (dexamethasone ~90%). The primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. A key secondary endpoint was all-cause mortality by day 28. Results: Overall, 27.8% of participants receiving baricitinib vs 30.5% receiving placebo progressed (primary endpoint, odds ratio 0.85, 95% CI 0.67-1.08; p=0.18). The 28-day all-cause mortality was 8.1% for baricitinib and 13.1% for placebo, corresponding to a 38.2% reduction in mortality (hazard ratio [HR] 0.57, 95% CI 0.41-0.78; nominal p=0.002); 1 additional death was prevented per 20 baricitinib-treated participants. Reduction in mortality was seen for all pre-specified subgroups of baseline severity (most pronounced for participants on high-flow oxygen/non-invasive ventilation at baseline [17.5%, baricitinib vs 29.4%, placebo; HR 0.52, 95% CI 0.33-0.80; nominal p=0.007]). The frequency of adverse events, serious adverse events, serious infections, and venous thromboembolic events was similar between groups. Conclusions: While reduction of disease progression did not achieve statistical significance, treatment with baricitinib in addition to SOC (predominantly dexamethasone) significantly reduced mortality with a similar safety profile between groups of hospitalized COVID-19 participants.

Background: The oral, selective Janus kinase (JAK)1/JAK2 inhibitor baricitinib demonstrated efficacy in hospitalised adults with COVID[ndash]19. This study evaluates the efficacy and safety of baricitinib in critically ill adults with COVID[ndash]19 requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). Methods: COV[ndash]BARRIER was a global, phase 3, randomised, double[ndash]blind, placebo[ndash]controlled trial in patients with confirmed SARS[ndash]CoV[ndash]2 infection (ClinicalTrials.gov NCT04421027). This addendum trial added a critically ill cohort not included in the main COV[ndash]BARRIER trial. Participants on baseline IMV/ECMO were randomly assigned 1:1 to baricitinib 4[ndash]mg (n=51) or placebo (n=50) for up to 14 days in combination with standard of care (SOC). Prespecified endpoints included all[ndash]cause mortality through days 28 and 60, and number of ventilator[ndash]free days, duration of hospitalisation, and time to recovery through day 28. Efficacy and safety analyses included the intent[ndash]to[ndash]treat and safety populations, respectively. Findings: SOC included baseline systemic corticosteroid use in 86% of participants. Treatment with baricitinib significantly reduced 28[ndash]day all[ndash]cause mortality compared to placebo (39[middot]2% vs 58[middot]0%; hazard ratio [HR]=0[middot]54 [95%CI 0[middot]31[ndash]0 [middot]96]; p=0[middot]030). One additional death was prevented for every six baricitinib[ndash]treated participants. Significant reduction in 60[ndash]day mortality was also observed (45[middot]1% vs 62[middot]0%; HR=0[middot]56 [95%CI 0[middot]33[ndash]0[middot]97]; p=0[middot]027). Baricitinib[ndash]treated participants showed numerically more ventilator[ndash]free days (8.1 vs 5.5 days, p=0.21) and spent over 2 days less in the hospital than placebo[ndash]treated participants (23[middot]7 vs 26[middot]1 days, p=0[middot]050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment arms. Interpretation: In critically ill patients with COVID[ndash]19 already receiving IMV/ECMO, treatment with baricitinib as compared to placebo (in combination with SOC, including corticosteroids) showed mortality HR of 0[middot]56, corresponding to a 44% relative reduction at 60 days. This is consistent with the mortality reduction observed in less severely ill hospitalised primary COV[ndash]BARRIER study population. Funding: Eli Lilly and Company.   Research in contextEvidence before this study We evaluated current and prior studies assessing the efficacy and safety of interventions in patients requiring invasive mechanical ventilation (IMV) and searched current PubMed using the terms [quot]COVID[ndash]19[quot], [quot]SARS[ndash]CoV[ndash]2[quot], [quot]treatment[quot], [quot]critical illness[quot], [quot]invasive mechanical ventilation[quot], [quot]baricitinib[quot], and [quot]JAK inhibitor[quot] for articles in English, published until December 1, 2020, regardless of article type. We also reviewed the NIH and IDSA COVID[ndash]19 guidelines and reviewed similar terms on clinicaltrials.gov. When the critical illness addendum study to COV[ndash]BARRIER study was designed, there was only one open[ndash]label study of dexamethasone showing mortality benefit in hospitalised patients with COVID[ndash]19 requiring IMV. Small studies of interleukin[ndash]6 inhibitors had shown no effect and larger trials were underway. Guidelines recommended use of dexamethasone with or without remdesivir and recommended against the use of interleukin[ndash]6 inhibitors, except in a clinical trial. Overall, there were no reported double[ndash]blind, placebo[ndash]controlled phase 3 trials which included corticosteroids as part of SOC investigating the efficacy and safety of novel treatments in the NIAID[ndash]OS 7 population. Baricitinib[apos]s mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID[ndash]19 given its known anti[ndash]cytokine properties and potential antiviral mechanism for targeting host proteins mediating viral endocytosis Data from the NIAID sponsored ACTT[ndash]2 trial showed that baricitinib when added to remdesivir improved time to recovery and other outcomes including mortality compared to placebo plus remdesivir. A numerically larger proportion of participants who received baricitinib plus remdesivir showed an improvement in ordinal scale compared to those who received placebo plus remdesivir at day 15 in participants requiring IMV (NIAID[ndash]OS score of 7) at baseline. We designed COV[ndash]BARRIER, a phase 3, global, double[ndash]blind, randomised, placebo[ndash]controlled trial, to evaluate the efficacy and safety of baricitinib in combination with SOC (including corticosteroids) for the treatment of hospitalised adults with COVID[ndash]19 who did not require mechanical ventilation (i.e., NIAID[ndash]OS 4[ndash]6). A significant reduction in mortality was found after 28 days between baricitinib and placebo (HR 0[middot]57, corresponding to a 43% relative reduction, p=0[middot]0018); one additional death was prevented per 20 baricitinib[ndash]treated participants. In the more severely ill NIAID[ndash]OS 6 subgroup, one additional death was prevented per nine baricitinib[ndash]treated participants (HR 0[middot]52, corresponding to a 48% relative reduction, p=0[middot]0065). We therefore implemented an addendum to the COV[ndash]BARRIER trial to evaluate the benefit/risk of baricitinib in the critically ill NIAID[ndash]OS 7 population and considered the sample size of 100 participants sufficient for this trial. Added value of this study This was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC), including antivirals, anticoagulants, and corticosteroids, in patients who were receiving IMV or extracorporeal membrane oxygenation at enrolment. This was a multinational, randomised, double[ndash]blind, placebo[ndash]controlled trial in regions with high COVID[ndash]19 hospitalisation rates. Treatment with baricitinib reduced 28[ndash]day all[ndash]cause mortality compared to placebo (HR 0[middot]54, 95% CI 0[middot]31[ndash]0[middot]96; nominal p=0[middot]030), corresponding to a 46% relative reduction, and significantly reduced 60[ndash]day all[ndash]cause mortality (HR 0[middot]56, 95% CI 0[middot]33[ndash]0[middot]97; p=0[middot]027); overall, one additional death was prevented per six baricitinib[ndash]treated participants. Numerical improvements in endpoints such as number of ventilator[ndash]free days, duration of hospitalisation, and time to recovery were demonstrated. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively. The COV[ndash]BARRIER study overall trial results plus these COV[ndash]BARRIER addendum study data in mechanically ventilated and ECMO patients provide important information in context of other large, phase 3 randomised trials in participants with invasive mechanical ventilation at baseline. The RECOVERY study reported mortality of 29[middot]3% following treatment with dexamethasone compared to 41[middot]4% for usual care (rate ratio of 0[middot]64, corresponding to a 36% relative reduction) and 49% mortality in participants who received tocilizumab compared to 51% for usual care (rate ratio of 0[middot]93, corresponding to a 7% relative reduction). The ACTT[ndash]2 study reported 28[ndash]day mortality of 23[middot]1% and 22[middot]6% in the baricitinib plus remdesivir and placebo plus remdesivir groups, respectively, in this critically ill patient population; however, the primary outcome of this trial was time to recovery, so was not powered to detect a change in mortality. Implications of all the available evidence In this phase 3 addendum trial, baricitinib given in addition to SOC (which predominantly included corticosteroids) had a significant effect on mortality reduction by 28 days in critically ill patients, an effect which was maintained by 60 days. These data were comparable with those seen in the COV[ndash]BARRIER primary study population of hospitalised patients, but which excluded patients who required IMV or extracorporeal membrane oxygenation at enrolment. These findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on the available evidence, baricitinib is a novel treatment option to decrease mortality in hospitalised, critically ill patients with COVID[ndash]19 even when started late in the disease process after steroids, mechanical ventilation, and ECMO have already been implemented.

ImportanceSARS-CoV-2, which causes COVID-19, poses considerable morbidity and mortality risks. Studies using data collected during routine clinical practice can supplement randomized clinical trials to provide needed evidence, especially during a global pandemic, and can yield markedly larger sample sizes to assess outcomes for important patient subgroups.ObjectiveTo evaluate the association of remdesivir treatment with inpatient mortality among patients with COVID-19 outside of the clinical trial setting.Design, Setting, and ParticipantsA retrospective cohort study in US hospitals using health insurance claims data linked to hospital chargemaster data from December 1, 2018, to May 3, 2021, was conducted among 24 856 adults hospitalized between May 1, 2020, and May 3, 2021, with newly diagnosed COVID-19 who received remdesivir and 24 856 propensity score–matched control patients.ExposureRemdesivir treatment.Main Outcomes and MeasuresAll-cause inpatient mortality within 28 days of the start of remdesivir treatment for the remdesivir-exposed group or the matched index date for the control group.ResultsA total of 24 856 remdesivir-exposed patients (12 596 men [50.7%]; mean [SD] age, 66.8 [15.4] years) and 24 856 propensity score–matched control patients (12 621 men [50.8%]; mean [SD] age, 66.8 [15.4] years) were included in the study. Median follow-up was 6 days (IQR, 4-11 days) in the remdesivir group and 5 days (IQR, 2-10 days) in the control group. There were 3557 mortality events (14.3%) in the remdesivir group and 3775 mortality events (15.2%) in the control group. The 28-day mortality rate was 0.5 per person-month in the remdesivir group and 0.6 per person-month in the control group. Remdesivir treatment was associated with a statistically significant 17% reduction in inpatient mortality among patients hospitalized with COVID-19 compared with propensity score–matched control patients (hazard ratio, 0.83 [95% CI, 0.79-0.87]).Conclusions and RelevanceIn this retrospective cohort study using health insurance claims and hospital chargemaster data, remdesivir treatment was associated with a significantly reduced inpatient mortality overall among patients hospitalized with COVID-19. Results of this analysis using data collected during routine clinical practice and state-of-the-art methods complement results from randomized clinical trials. Future areas of research include assessing the association of remdesivir treatment with inpatient mortality during the circulation of different variants and relative to time from symptom onset.