C reactive protein utilisation, a biomarker for early COVID-19 treatment, improves lenzilumab efficacy: results from the randomised phase 3 ‘LIVE-AIR’ trial
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Abstract
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
Article activity feed
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SciScore for 10.1101/2021.12.30.21267140: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: 15 Enrolled participants were randomized 1:1 to receive lenzilumab or matched placebo in addition to current standard treatments per institutional guidelines at each site. Sex as a biological variable not detected. Randomization Trial Design: LIVE-AIR is a randomized, double-blind, placebo-controlled, phase 3 trial (NCT04351152) and enrolled hospitalized participants with COVID-19 pneumonia. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected …SciScore for 10.1101/2021.12.30.21267140: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: 15 Enrolled participants were randomized 1:1 to receive lenzilumab or matched placebo in addition to current standard treatments per institutional guidelines at each site. Sex as a biological variable not detected. Randomization Trial Design: LIVE-AIR is a randomized, double-blind, placebo-controlled, phase 3 trial (NCT04351152) and enrolled hospitalized participants with COVID-19 pneumonia. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:12 Limitations are associated with the analytic approach herein. The exploratory analysis of CRP as it relates to the primary endpoint of the likelihood of achieving SWOV was pre-specified, all other analyses were post-hoc, and none were prospectively powered. Therefore, the results should be interpreted with this caveat in mind. The findings herein will be further evaluated in the NIH-sponsored ACTIV-5/BET-B trial, that includes lenzilumab and where the primary efficacy analysis prospectively evaluates incidence of IMV, ECMO, or death in participants with baseline CRP<150 mg/L. In summary, this comprehensive analysis of LIVE-AIR CRP data provides evidence for the utility of CRP to predict progression to IMV and death. GM-CSF neutralization with lenzilumab significantly improved SWOV in adults hospitalized with COVID-19 pneumonia compared to placebo. Those participants who had baseline CRP levels <150 mg/L responded more favorably to lenzilumab treatment, than those with CRP>150 mg/L. These finding suggest that CRP may be a useful biomarker in determining which participants may be most successfully treated with lenzilumab.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04351152 Active, not recruiting Phase 3 Study to Evaluate Efficacy and Safety of Lenzilumab … NCT04280705 Completed Adaptive COVID-19 Treatment Trial (ACTT) Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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