Baricitinib plus Standard of Care for Hospitalised Adults with COVID-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: Results of a Randomized, Placebo-Controlled Trial.

ABSTRACT

BackgroundThe oral, selective Janus kinase (JAK)1/JAK2 inhibitor baricitinib demonstrated efficacy in hospitalised adults with COVID-19. This study evaluates the efficacy and safety of baricitinib in critically ill adults with COVID-19 requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). MethodsCOV-BARRIER was a global, phase 3, randomised, double-blind, placebo-controlled trial in patients with confirmed SARS-CoV-2 infection (ClinicalTrials.gov NCT04421027). This addendum trial added a critically ill cohort not included in the main COV-BARRIER trial. Participants on baseline IMV/ECMO were randomly assigned 11 to baricitinib 4-mg (n=51) or placebo (n=50) for up to 14 days in combination with standard of care (SOC). Prespecified endpoints included all-cause mortality through days 28 and 60, and number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively. FindingsSOC included baseline systemic corticosteroid use in 86% of participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared to placebo (39{middle dot}2% vs 58{middle dot}0%; hazard ratio [HR]=0{middle dot}54 [95%CI 0{middle dot}31-0{middle dot}96]; p=0{middle dot}030). One additional death was prevented for every six baricitinib-treated participants. Significant reduction in 60-day mortality was also observed (45{middle dot}1% vs 62{middle dot}0%; HR=0{middle dot}56 [95%CI 0{middle dot}33-0{middle dot}97]; p=0{middle dot}027). Baricitinib-treated participants showed numerically more ventilator-free days (8.1 vs 5.5 days, p=0.21) and spent over 2 days less in the hospital than placebo-treated participants (23{middle dot}7 vs 26{middle dot}1 days, p=0{middle dot}050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment arms. InterpretationIn critically ill patients with COVID-19 already receiving IMV/ECMO, treatment with baricitinib as compared to placebo (in combination with SOC, including corticosteroids) showed mortality HR of 0{middle dot}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-BARRIER study population. FundingEli Lilly and Company. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe 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 "COVID-19", "SARS-CoV-2", "treatment", "critical illness", "invasive mechanical ventilation", "baricitinib", and "JAK inhibitor" for articles in English, published until December 1, 2020, regardless of article type. We also reviewed the NIH and IDSA COVID-19 guidelines and reviewed similar terms on clinicaltrials.gov. When the critical illness addendum study to COV-BARRIER study was designed, there was only one open-label study of dexamethasone showing mortality benefit in hospitalised patients with COVID-19 requiring IMV. Small studies of interleukin-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-6 inhibitors, except in a clinical trial. Overall, there were no reported double-blind, placebo-controlled phase 3 trials which included corticosteroids as part of SOC investigating the efficacy and safety of novel treatments in the NIAID-OS 7 population. Baricitinibs mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID-19 given its known anti-cytokine properties and potential antiviral mechanism for targeting host proteins mediating viral endocytosis Data from the NIAID sponsored ACTT-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-OS score of 7) at baseline. We designed COV-BARRIER, a phase 3, global, double-blind, randomised, placebo-controlled trial, to evaluate the efficacy and safety of baricitinib in combination with SOC (including corticosteroids) for the treatment of hospitalised adults with COVID-19 who did not require mechanical ventilation (i.e., NIAID-OS 4-6). A significant reduction in mortality was found after 28 days between baricitinib and placebo (HR 0{middle dot}57, corresponding to a 43% relative reduction, p=0{middle dot}0018); one additional death was prevented per 20 baricitinib-treated participants. In the more severely ill NIAID-OS 6 subgroup, one additional death was prevented per nine baricitinib-treated participants (HR 0{middle dot}52, corresponding to a 48% relative reduction, p=0{middle dot}0065). We therefore implemented an addendum to the COV-BARRIER trial to evaluate the benefit/risk of baricitinib in the critically ill NIAID-OS 7 population and considered the sample size of 100 participants sufficient for this trial. Added value of this studyThis 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-blind, placebo-controlled trial in regions with high COVID-19 hospitalisation rates. Treatment with baricitinib reduced 28-day all-cause mortality compared to placebo (HR 0{middle dot}54, 95% CI 0{middle dot}31-0{middle dot}96; nominal p=0{middle dot}030), corresponding to a 46% relative reduction, and significantly reduced 60-day all-cause mortality (HR 0{middle dot}56, 95% CI 0{middle dot}33-0{middle dot}97; p=0{middle dot}027); overall, one additional death was prevented per six baricitinib-treated participants. Numerical improvements in endpoints such as number of ventilator-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-BARRIER study overall trial results plus these COV-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{middle dot}3% following treatment with dexamethasone compared to 41{middle dot}4% for usual care (rate ratio of 0{middle dot}64, corresponding to a 36% relative reduction) and 49% mortality in participants who received tocilizumab compared to 51% for usual care (rate ratio of 0.93, corresponding to a 7% relative reduction). The ACTT-2 study reported 28-day mortality of 23{middle dot}1% and 22{middle dot}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 evidenceIn 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-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-19 even when started late in the disease process after steroids, mechanical ventilation, and ECMO have already been implemented.