LENZILUMAB EFFICACY AND SAFETY IN NEWLY HOSPITALIZED COVID-19 SUBJECTS: RESULTS FROM THE LIVE-AIR PHASE 3 RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL
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Abstract
BACKGROUND
Severe COVID-19 pneumonia results from a hyperinflammatory immune response (cytokine storm, CS), characterized by GM-CSF mediated activation and trafficking of myeloid cells, leading to elevation of downstream inflammatory chemokines (MCP-1, IL-8, IP-10), cytokines (IL-6, IL-1), and other markers of systemic inflammation (CRP, D-dimer, ferritin). CS leads to fever, hypotension, coagulopathy, respiratory failure, ARDS, and death. Lenzilumab is a novel Humaneered ® anti-human GM-CSF monoclonal antibody that directly binds GM-CSF and prevents signaling through its receptor. The LIVE-AIR Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to assess the potential for lenzilumab to improve the likelihood of ventilator-free survival (referred to herein as survival without ventilation, SWOV), beyond standard supportive care, in hospitalized subjects with severe COVID-19.
METHODS
Subjects with COVID-19 (n=520), ≥18 years, and ≤94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Subjects were followed through Day 28 following treatment.
RESULTS
Baseline demographics were comparable between the two treatment groups: male, 64.7%; mean age, 60.5 years; mean BMI, 32.5 kg/m 2 ; mean CRP, 98.36 mg/L; CRP was <150 mg/L in 77.9% of subjects. The most common comorbidities were obesity (55.1%), diabetes (53.4%), chronic kidney disease (14.0%), and coronary artery disease (13.6%). Subjects received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the likelihood of SWOV by 54% in the mITT population (HR: 1.54; 95%CI: 1.02-2.31, p=0.041) and by 90% in the ITT population (HR: 1.90; 1.02-3.52, nominal p=0.043) compared to placebo. SWOV also relatively improved by 92% in subjects who received both corticosteroids and remdesivir (1.92; 1.20-3.07, nominal p=0.0067); by 2.96-fold in subjects with CRP<150 mg/L and age <85 years (2.96; 1.63–5.37, nominal p=0.0003); and by 88% in subjects hospitalized ≤2 days prior to randomization (1.88; 1.13-3.12, nominal p=0.015). Survival was improved by 2.17-fold in subjects with CRP<150 mg/L and age <85 years (2.17; 1.04-4.54, nominal p=0.040).
CONCLUSION
Lenzilumab significantly improved SWOV in hospitalized, hypoxic subjects with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Subjects with CRP<150 mg/L and age <85 years demonstrated an improvement in survival and had the greatest benefit from lenzilumab. NCT04351152
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SciScore for 10.1101/2021.05.01.21256470: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The protocol was approved by the central/local institutional review board or ethics committee at each site.
Consent: All subjects provided written informed consent.
IACUC: Enrolled participants were randomized 1:1 to receive lenzilumab or matched placebo in addition to current standard treatment per institutional guidelines at each site.Sex as a biological variable Women of childbearing potential were eligible if they had a negative urine or serum pregnancy test at screening/baseline and agreed to adequate contraception following their last dose of study drug. Randomization Trial Design: The LIVE-AIR trial (NCT04351152) was a phase 3 randomized, double-blind, placebo-controlled study in … SciScore for 10.1101/2021.05.01.21256470: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The protocol was approved by the central/local institutional review board or ethics committee at each site.
Consent: All subjects provided written informed consent.
IACUC: Enrolled participants were randomized 1:1 to receive lenzilumab or matched placebo in addition to current standard treatment per institutional guidelines at each site.Sex as a biological variable Women of childbearing potential were eligible if they had a negative urine or serum pregnancy test at screening/baseline and agreed to adequate contraception following their last dose of study drug. Randomization Trial Design: The LIVE-AIR trial (NCT04351152) was a phase 3 randomized, double-blind, placebo-controlled study in 520 hospitalized subjects with severe COVID-19 pneumonia across 29 sites in the U.S. and Brazil. Blinding not detected. Power Analysis 21-23 The event rate of subjects who required IMV or died by Day 28 in the placebo group was estimated to be approximately 25%, and the event rate in the lenzilumab treatment group was approximated as 15% resulting in a HR of 0.565.24 Using a Cox proportional hazard model to test for inequality of the HR, a total of 100 events were calculated as needed to provide 81.47% power to detect a difference using a two-sided alpha of 5.0% at the final analysis and assuming a fixed follow-up of 28 days. Table 2: Resources
Antibodies Sentences Resources Disallowed medications were FDA-approved monoclonal antibodies targeting IL-6 or IL-1, kinase inhibitors, and COVID-19 neutralizing monoclonal antibodies if used within 8 weeks prior to randomization. IL-6suggested: NoneIL-1suggested: NoneResults 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:LIVE-AIR has two important limitations. First, while it demonstrated an improvement in survival in subjects with CRP<150 mg/L and aged <85, the study was not powered to observe a survival benefit, and indeed did not achieve statistical significance on this key secondary endpoint in the mITT population. Second, the observations pertaining to benefits in the population that had CRP<150 mg/L and age <85 were exploratory. Despite high vaccine efficacy and uptake in some countries, hospitalizations for COVID-19 will continue to occur given the propensity for mutation and escape from protection that occurs through natural immunological selection.34 A proportion of those subjects will unfortunately progress to hypoxia and hospitalization. For them, dexamethasone is currently the only treatment approach shown to provide a survival benefit. This study demonstrates that early neutralization of GM-CSF with lenzilumab, a key initiator and orchestrator of CS, in newly hospitalized hypoxic subjects can improve their likelihood of survival without the need for mechanical ventilation and defines a targeted patient population most likely to derive the greatest benefit over and above that of steroids and/or remdesivir.
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) NCT04376684 Recruiting Investigating Otilimab in Patients With Severe Pulmonary COV… 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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