Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial

Abstract

Background: The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments.

Methods: In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04351152, and is completed.

Findings: Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41-137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79-89) participants in the lenzilumab group and in 190 (78%; 72-83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02-2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death.

Interpretation: Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown.

Funding: Humanigen.

Figure 1

Trial profile The intention-to-treat population consisted of all randomised patients. *The safety set included all patients who received at least one dose of study drug and is presented by the actual drug received; safety was assessed on study drug received, regardless of assignment group. Eight randomly assigned patients were never treated and were therefore excluded from the safety analysis but were included in the intention-to-treat analyses. †Randomly assigned patients who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator were included in the modified intention-to-treat population. This population excluded patients from sites that had documented limitations in terms of access to basic supportive care for COVID-19. One patient, randomly assigned to placebo, received lenzilumab in error and was included in the safety analysis of lenzilumab and in the modified intention-to-treat efficacy analysis of placebo.

Figure 2

Kaplan-Meier plot of survival without invasive mechanical ventilation and its individual components (A) Plot for survival without invasive mechanical ventilation in the mITT population. The mITT analysis was the primary efficacy analysis. Separation of the survival curves occurred as early as 3 days following treatment. Following day 10, separation was maintained for the duration of the observation period. (B) Plot for invasive mechanical ventilation. (C) Plot for mortality. mITT=modified intention-to-treat.