C reactive protein utilisation, a biomarker for early COVID-19 treatment, improves lenzilumab efficacy: results from the randomised phase 3 'LIVE-AIR' trial

Abstract

Objective: COVID-19 severity is correlated with granulocyte macrophage colony-stimulating factor (GM-CSF) and C reactive protein (CRP) levels. In the phase three LIVE-AIR trial, lenzilumab an anti-GM-CSF monoclonal antibody, improved the likelihood of survival without ventilation (SWOV) in COVID-19, with the greatest effect in participants having baseline CRP below a median of 79 mg/L. Herein, the utility of baseline CRP to guide lenzilumab treatment was assessed.

Design: A subanalysis of the randomised, blinded, controlled, LIVE-AIR trial in which lenzilumab or placebo was administered on day 0 and participants were followed through Day 28.

Participants: Hospitalised COVID-19 participants (N=520) with SpO2 ≤94% on room air or requiring supplemental oxygen but not invasive mechanical ventilation.

Interventions: Lenzilumab (1800 mg; three divided doses, q8h, within 24 hours) or placebo infusion alongside corticosteroid and remdesivir treatments.

Main outcome measures: The primary endpoint was the time-to-event analysis difference in SWOV through day 28 between lenzilumab and placebo treatments, stratified by baseline CRP.

Results: SWOV was achieved in 152 (90%; 95% CI 85 to 94) lenzilumab and 144 (79%; 72 to 84) placebo-treated participants with baseline CRP <150 mg/L (HR: 2.54; 95% CI 1.46 to 4.41; p=0.0009) but not with CRP ≥150 mg/L (HR: 1.04; 95% CI 0.51 to 2.14; p=0.9058). A statistically significant interaction between CRP and lenzilumab treatment was observed (p=0.044). Grade ≥3 adverse events with lenzilumab were comparable to placebo in both CRP strata. No treatment-emergent serious adverse events were attributed to lenzilumab.

Conclusion: Hospitalised hypoxemic patients with COVID-19 with baseline CRP <150 mg/L derived the greatest clinical benefit from treatment with lenzilumab.

Trial registration number: NCT04351152; ClinicalTrials.gov.

Keywords: ARDS; COVID-19; Critical Care; Cytokine Biology; GM-CSF; Pneumonia; Respiratory Infection.

Figure 1

Randomisation and analysis populations. Eight participants were ineligible to participate as they either declined participation or withdrew consent. Broad inclusion criteria allowed for the remainder of the participants to be randomised. The ITT population consisted of all randomised participants. The safety set included all participants who received at least one dose of the study drug and is presented by the actual drug received. Randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator were included in the mITT population. This population excluded participants from sites that experienced documented limitations to access of basic supportive care for COVID-19. ITT, intent to treat; mITT, modified ITT. SOC represents standard of care

Figure 2

Kaplan-Meier estimate for survival without ventilation. (A) KM estimate for survival without ventilation (primary endpoint). The primary efficacy analysis was based on the overall mITT population. Separation of the survival curves occurred as early as 3 days following treatment. Following day 10, separation maintained for the duration of the observation period. Lenzilumab treatment improved the relative likelihood of achieving SWOV compared with placebo (HR: 1.54; 95% CI: 1.02 to 2.32, p=0.0403). The log-rank p-value=0.0457. Reprinted from Lancet Respiratory Medicine. Temesgen Z, Burger CD, Baker J, Polk C, Libertin CR, Kelley CF, Marconi VC, Orenstein R, Catterson VM, Aronstein WS, Durrant CD, Chappell, D, Ahmed O, Chappell G, Badley AD, for the LIVE-AIR Study Group, Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial, DOI:https://doi.org/10.1016/S2213-2600(21)00 494-X, Copyright (2021), with permission from Elsevier. (B). KM estimate for survival without ventilation in participants with baseline CRP <150 mg/L. Separation of the survival curves occurred after 2 days post treatment. The separation of the curves was more pronounced than in the overall mITT analysis. Lenzilumab treatment improved the relative likelihood of achieving SWOV compared with placebo (HR: 2.54; 95% CI: 1.46 to 4.41, p=0.0009). The log-rank p-value=0.0002. (C) KM estimate for survival without ventilation in participants with baseline CRP ≥150 mg/L. The survival curves fail to separate through the 28-day follow-up period (HR: 1.04; 95% CI: 0.51 to 2.14, p=0.9058). The log-rank p-value=0.4938. ITT, intent to treat; mITT, modified ITT; SWOV, survival without ventilation.

Figure 3

Impact of baseline demographics and risk factors on survival without ventilation using an iterative multivariate logistic regression model. A multi-variate logistic regression analysis was conducted to assess known key risk factors for progression to IMV or death. Logistic regression models were built to predict Day 28 SWOV using known risk factors for progression to IMV or death that were available in the intent-to-treat (ITT) dataset. Three versions of the model were built: one with baseline ordinal score and not severity (stratification variable: severe or critical), one with severity and not baseline ordinal scale, and one with neither baseline ordinal scale nor severity. The set of covariates included in the models were: lenzilumab or placebo treatment; age ≥ 65 or <65 years; gender; linear transformed BMI (BMI 17=0.0, BMI 45=1.0); number of days before randomization of symptom onset (SYMDAY); number of days before randomization of hospital admission (DIADAY); baseline CRP; diabetes; heart condition: prior diagnosis of hypertension, coronary artery disease, or congestive heart failure; respiratory condition: prior diagnosis of asthma, COPD, or interstitial lung disease; vascular condition: prior diagnosis of cerebrovascular disorders or thrombosis and embolism; other risk factors: prior diagnosis of cancers (haematological or non-haematological), chronic kidney disease (including renal failure), chronic liver disease (including hepatic failure), or being a smoker. Model type training was performed by bootstrapping, where 10,000 logistic regression models were built on random subsets of the ITT analysis set (n=520). For each bootstrapped model iteration, metrics were evaluated on the 20% test set and the feature coefficients of the model were recorded. This gave a distribution of 10,000 samples for the metrics and coefficients. All models produced similar outcomes. Therefore, the model chosen used severity as the covariate to be consistent with the covariate used in the pre-specified primary analysis, in addition to the other risk factors as covariates. Statistical significance was reached for all features with a displayed p-value. CRP, C reactive protein.

Figure 4

Likelihood of survival without ventilation by level of CRP Cut-off. The HR for SWOV was calculated for all participants, with CRP level below the indicated cut-off value. Participants with CRP <150 mg/L had the greatest likelihood of achieving SWOV. CRP, C reactive protein; SWOV, survival without ventilation.

Figure 5

Analysis of CRP levels over time through day 28. (A) CRP levels over time in participants who met primary endpoint (SWOV) versus participants who progressed to IMV and/or death. This analysis was conducted on the entire mITT population without regard to treatment. CRP levels in participants requiring IMV or who died remained elevated through the hospital course. CRP levels were lower in participants who achieved SWOV. (B) CRP levels over time in participants treated with lenzilumab versus placebo. Lenzilumab decreased plasma CRP levels relative to placebo by day 7 and through day 14 following treatment. (Values are mean±SE; mITT population). CRP, C reactive protein; ITT, intent to treat; IMV, invasive mechanical ventilation; mITT, modified ITT; SWOV, survival without ventilation.