ABSTRACT
RATIONALEThe hyperinflammatory immune response of COVID-19, in part orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF) can lead to respiratory failure and death with disparities in outcomes between racial subgroups. In the LIVE-AIR trial, the GM-CSF neutralizing antibody lenzilumab improved survival without mechanical ventilation (SWOV) in COVID-19. OBJECTIVEAn analysis of outcomes was performed to determine differences between Black/African American (B/AA) and White participants in LIVE-AIR. METHODSLIVE-AIR was a phase 3, randomized, double-blind, placebo-controlled trial. Participants hospitalized with COVID-19 pneumonia were randomized 1:1 to receive lenzilumab (1800 mg total) or placebo in addition to standard of care, including remdesivir and/or corticosteroids. MEASUREMENTS AND MAIN RESULTSLenzilumab, compared to placebo, numerically improved the likelihood of SWOV (primary endpoint) in B/AA (n=71; 86.8% vs 70.9%; HR, 2.68; 95% confidence interval [CI], 0.88-8.11; p=0.0814) and White (n=343; 85.1% vs 80.8%; HR, 1.41; 95%CI, 0.85-2.35, p=0.182) participants. A statistically significant improvement in SWOV was observed in B/AA (HR: 8.9; 95%CI: 1.08, 73.09; p=0.0418) and White (HR: 2.32; 95%CI: 1.17, 4.61; p=0.0166) participants with baseline CRP<150 mg/L. Lenzilumab numerically, but not statistically, improved secondary endpoints of IMV, ECMO or mortality; ventilator-free days; ICU days and time to recovery in either race while ventilator-free days, ICU days, and time to recovery were statistically improved in B/AA participants with baseline CRP<150 mg/L. Lenzilumab was well tolerated without differences in serious adverse events regardless of race. CONCLUSIONLenzilumab significantly improved SWOV and some key secondary outcomes in B/AA COVID-19 participants with baseline CRP<150 mg/L. NCT04351152
ABSTRACT
ObjectiveThe LIVE-AIR trial demonstrated that the anti-GM-CSF monoclonal antibody, lenzilumab improved the likelihood of survival without invasive mechanical ventilation (SWOV) in COVID-19 patients; with greatest effect in those with baseline CRP below the median baseline value of 79 mg/L. Similar to GM-CSF, C-reactive protein (CRP) levels are correlated with COVID-19 severity. This current analysis assessed the utility of baseline CRP levels to guide treatment with lenzilumab. DesignLIVE-AIR was a phase 3, double-blind, placebo-controlled trial. Participants were randomized 1:1 and stratified according to age and disease severity, to receive lenzilumab or placebo on Day 0, were followed through Day 28. SettingSecondary and tertiary care hospitals in the US and Brazil. Participants520 hospitalized COVID-19 participants with SpO2[≤] 94% on room air or required supplemental oxygen but not invasive mechanical ventilation were included. InterventionsLenzilumab (1800mg; divided as 3 doses, q8h) or placebo infusion alongside standard treatments including corticosteroids and remdesivir. Main outcome measuresA multi-variate logistic regression analysis assessed key baseline risk factors for progression to IMV or death. The primary endpoint, SWOV, and key secondary endpoints were analyzed according to baseline CRP levels in all participants with CRP values. ResultsThe multi-variate analysis demonstrated that elevated baseline plasma CRP was the most predictive feature for progression to IMV or death. SWOV was achieved in 152 (90%; 95%CI: 85to 94) lenzilumab and 183 (79%; 72 to 84) placebo participants with baseline CRP<150 mg/L and its likelihood was greater with lenzilumab than placebo (HR: 2.54; 95%CI, 1.46 to 4.41; p=0.0009) but not in participants with CRP[≥]150 mg/L at baseline. CRP as a covariate in the overall analysis demonstrated a statistically significant interaction with lenzilumab treatment (p=0.044). Grade [≥] 3 adverse events in participants with baseline CRP<150 mg/L were reported in 18% and 28% in lenzilumab or placebo, respectively. No treatment-emergent serious adverse events were attributable to lenzilumab. ConclusionThese finding suggest that COVID-19 participants with low baseline CRP levels achieve the greatest clinical benefit from lenzilumab and that baseline CRP levels may be a useful biomarker to guide therapeutic intervention. Trial RegistrationClinicalTrials.gov NCT04351152 WHAT IS ALREADY KNOWN ON THIS TOPICGM-CSF is one of the early upstream mediators and orchestrators of the hyperinflammatory immune response following SARS-CoV-2 infection. Baseline levels of GM-CSF and CRP have each been shown to correlate with COVID-19 disease progression. Increases in CRP are driven by elevations of IL-6 during the hyperinflammatory response following SARS-CoV-2 infection. In the phase 3, randomized, double-blind, placebo-controlled LIVE-AIR study, GM-CSF neutralization with lenzilumab significantly improved the likelihood of survival without invasive mechanical ventilation (SWOV, primary endpoint, also referred to as ventilator-free survival) vs. placebo (HR:1.54; 95% CI, 1.02 to 2.32; p=0.0403), which included standard supportive care including corticosteroids and remdesivir. No treatment-emergent serious adverse events attributable to lenzilumab have been reported to date. WHAT THIS STUDY ADDSA comprehensive analysis of LIVE -AIR CRP data provides evidence for the utility of baseline CRP to predict progression to IMV and death. Baseline CRP was identified to be the strongest predictor of SWOV in this study. Patients with baseline CRP<150 mg/L represented 78% of the study population and demonstrated the greatest clinical benefit with lenzilumab, including SWOV through day 28 (HR: 2.54; 95%CI; 1.46-4.41; nominal p=0.0009). A biomarker-driven approach using baseline CRP levels to guide therapeutic intervention may improve outcomes in those hospitalized with COVID-19. Participants with baseline CRP levels above 150 mg/L were described as experiencing COVID-19-associated hyperinflammation and were at risk of imminent escalation of respiratory support or death. Elevated baseline plasma CRP was the most predictive feature for progression to IMV or death (OR, 0.15; 95%CI, 0.07-0.29; nominal p<0.001). These findings suggest that baseline CRP may be a useful biomarker in determining which participants may be most successfully treated with lenzilumab.
ABSTRACT
ObjectivesTo determine whether early oral or parenteral corticosteroids compared to no corticosteroids are associated with decreased mortality in patients hospitalized with coronavirus disease 2019 (COVID-19) who are not on intensive respiratory support (IRS) within 48 hours of admission. DesignObservational cohort study SettingNationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated US national healthcare system Participants9,058 patients admitted to a Veterans Affairs Medical Center between June 7, 2020-December 5, 2020 within 14-days after SARS-CoV-2 positive test; exclusion criteria include less than a 48 hour stay, receipt of prior systemic corticosteroids, and no indication of acute medical care for COVID-19. Main outcome measure90-day all-cause mortality ResultsOf 9,058 total patients (95% men, median age 71 years, 27% black), 6,825 (75%) were not on IRS within 48 hours. Among the 3,025 patients on no oxygen, 598 (20%) received corticosteroids and 283 (9%) died; of 3,800 patients on low-flow nasal cannula oxygen (NC), 2,808 (74%) received corticosteroids and 514 (13%) died. In stratified, inverse probability weighted Cox proportional hazards models comparing those who did and did not receive corticosteroids, patients on no oxygen experienced an 89% increased risk for 90-day mortality (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.33 to 2.68); there was weak evidence of increased mortality among patients on NC (HR 1.21, 95% CI 0.94 to 1.57). Results were robust in subgroup analyses including restricting corticosteroids to dexamethasone, and in sensitivity analyses employing different modeling approaches. ConclusionsIn patients hospitalized with COVID-19, we found no evidence of a mortality benefit associated with early initiation of corticosteroids among those on no oxygen or NC in the first 48 hours, though there was evidence of potential harm. These real-world findings support that clinicians should consider withholding corticosteroids in these populations and further clinical trials may be warranted.
