Paper: Temesgen Z et al. Lenzilumab Efficacy and Safety in Newly Hospitalized COVID-19 Subjects: Results from the LIVE-AIR Phase 3 Randomized Double-Blind Placebo-Controlled Trial. medRxiv 2021. [Preprint]
Clinical Question: Can Lenzilumab decrease survival without ventilation (SWOV) compared to placebo in hospitalized patients not requiring invasive mechanical ventilation with COVID-19?
What They Did:
- LIVE-AIR
- Lenzilumab
- Improves the Likelihood of Survival Without
- Ventilation in Newly Hospitalized Subjects
- Exploring CRP <150mg/L
- Age Less than 85 years, with active
- Inflammation
- Requiring Oxygen
- Phase 3, randomized, double-blind, placebo-controlled clinical trial
- Testing the efficacy and safety of lenzilumab
- 520 hospitalized pts with severe COVID-19 pneumonia across 29 sites in the US and Brazil
- Patient randomized 1:1 to:
- Lenzilumab 600mg
- Matched Placebo (saline)
- Both via three IV infusions over 1hr administered 8hrs apart
- Patients were followed through 28d after treatment
- ITT =
- All patients that consented and were screened
- Removed patients that were ineligible or declined to participate
- 520pts
- mITT =
- Same group of patients as ITT, but removed patients that:
- Were randomized but not given medication
- Had no oversight by investigator
- Had documented limitations to access of basic supportive care for COVID-19 (i.e. HFNC, or NPPV)
- 479pts
- Same group of patients as ITT, but removed patients that:
Outcomes:
- Primary: Composite endpoint of Survival WithOut Ventilation (SWOV) at day 28 – aka ventilator-free survival
- Failure defined as mortality or requirement of IMV
- Performed on:
- All enrolled pts
- Pts with CRP <150mg/L and age <85 years
- Received remdesivir and/or any corticosteroid
- Randomized ≤2d from hospitalization and >2d from hospitalization
- Key Secondary Endpoints:
- Proportion of:
- IMV
- ECMO
- Death/Mortality
- Time to recovery based on an 8 point clinical status scale
- 1 = death
- 8 = No hospitalization, no limitations
- Proportion of:
Inclusion:
- ≥18 years of age
- SARS-CoV-2 infection confirmed
- Pneumonia diagnosed by CXR or CT chest
- ≤94% on RA and/or requiring supplemental O2 BUT not invasive mechanical ventilation
Exclusion:
- Requiring invasive mechanical ventilation (IMV) or ECMO
- Pregnant
- If not expected to survive the following 48hrs from time of randomization
- Confirmed bacterial pneumonia
- Active/uncontrolled fungal or viral infection other than SARS-CoV-2
Results:
- 520 patients with COVID-19 enrolled and randomized into the ITT population
- 41pts (7.9%) excluded for the mITT population due to an unexpected surge of patients leading to an inability to provide basic care
- At randomization:
- 5% of pts were ordinal score 3 (high flow oxygen or NPPV)
- 5% of pts were ordinal score 4 (low flow oxygen) or ordinal score 5 (SpO2<94% on RA)
- Common standard care medications given:
- 7% received steroids
- 4% received remdesivir
- 1% received both
- Survival Without Ventilation (SWOV) Compared to Placebo (Primary Endpoint):
- mITT
- Lenzilumab: 15.6%
- Placebo: 22.1%
- HR 1.54; 95% CI 1.02 – 2.31; p = 0.041
- ITT
- Lenzilumab: 18.9%
- Placebo: 23.6%
- HR 1.90; 95% CI 1.02 – 3.52; p = 0.043
- Results confirmed on multiple sensitivity analyses
- mITT
- Survival Without Ventilation (SWOV) Compared to Placebo in Pts with CRP <150mg/L and Age <85yrs (Exploratory Analysis):
- mITT
- Lenzilumab: 8.5%
- Placebo: 21.1%
- HR 2.96; 95% CI 1.63 – 5.37; p = 0.0003
- ITT
- Lenzilumab: 11.5%
- Placebo: 22.6%
- HR 2.23; 95% CI 1.32 – 3.75; p = 0.0030
- mITT
- Incidence of IMV, ECMO, or Death:
- Lenzilumab: 15.4%
- Placebo: 21.4%
- OR 0.67; 95% CI 0.41 to 1.10; p = 0.111
- Incidence of IMV, ECMO, or Death in Pts with CRP <150mg/L and Age <85yrs (Exploratory Analysis):
- Lenzilumab: 7.2%
- Placebo 19.5%
- OR 0.32; 95% CI 0.15 to 0.65; p = 0.002
- Mortality:
- Lenzilumab: 9.6%
- Placebo: 13.9%
- OR 1.38; 95% CI 0.81 – 2.37; p = 0.239
- Mortality in Pts with CRP <150mg/L and Age <85yrs (Exploratory Analysis):
- Lenzilumab: 6.6%
- Placebo: 13.8%
- OR 2.17; 95% CI 1.04 – 4.54; p = 0.40
- Severe Adverse Events:
- Lenzilumab: 24.7%
- Placebo: 29.6%
- No infusion related reactions and no attributable serious adverse events with Lenzilumab compared with placebo (including increased incidence of infection)
Strengths:
- Multicenter, randomized, double-blind, clinical trial
- Despite being in a pandemic only had <2% loss to follow up in each arm
- 100% source data verification and adherence to good clinical practices
- Baseline characteristics were well balanced between groups
Limitations:
- SWOV is a composite, subjective, surrogate outcome. The indications to intubate are most likely different at each institution
- Not clear how randomization was performed
- Most patients were not critically ill at baseline (i.e. Most on minimal if any O2 support)
- No information on whether outcomes varied by country or hospital which is important given limitations during surge in Brazil. The effects of lenzilumab in the US were considerably lower
- Enrollment was not consecutive, making this a convenience sample
- Study not powered appropriately for mortality outcomes. Additionally study powered at 91.47% to find a 10% difference. This power is relatively low (i.e. typically see 90 or 95%)
- Results pertaining to benefits in the population with a CRP<150mg/L and age <85 years are exploratory and therefore hypothesis generating at this time
- Unclear how vaccine uptake has also affected the results of this trial. Is the benefit seen from the medication lenzilumab or from increased vaccine uptake? Unclear how this would have affected the study
Discussion:
- Lenzilumab falls under the new interesting treatment therapies for COVID-19
- Can be given early in hospitalization course (targeting GM-CSF early during the emerging hyperinflammatory stage in order to potentially ameliorate cytokine storm)
- Survival without ventilation was more than with corticosteroids alone (? Synergistic effect)
- Treatment was safe and well tolerated with a serious adverse event profile no different from placebo
- CRP and Age CAVEAT: CRP <150mg/L and age <85 years is a niche population
- Have to watch out for indication creep (Effect not as robust in all comers)
- These results are hypothesis generating as they are exploratory analyses (study not intended nor powered for these outcomes)
- 77% of patients had an elevated CRP at baseline with a value of <150mg/L and 74% had baseline CRP value <150mg/L and age <85years
- CRP <150mg/L was associated with best likelihood of achieving SWOV
- CRP<150mg/L and age <85years improved SWOV by nearly 3-fold and mortality by 2.17-fold
- CRP <150mg/L can potentially help differentiate emerging hyperinflammation from full-blown cytokine storm
- It’s unclear why hazard ratios were used, when the authors could just do absolute differences and use NNTs. Using HRs tends to make the difference look bigger (50% relative difference) when actually the absolute difference is more modest (but still important) ≈6% which gives a NNT of about 16
Author 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 <150mg/L and age <85 years demonstrated an improvement in survival and had the greatest benefit from lenzilumab.”
Clinical Take Home Point: Lenzilumab is a new and interesting treatment for hospitalized patients with COVID-19 not requiring invasive mechanical ventilation. Both the primary and exploratory analyses showed benefit in decreasing SWOV, however the benefit was more modest in the overall patient population compared to the exploratory analyses. Additionally, this study was not intended nor powered for these exploratory outcomes.
References:
- Temesgen Z et al. Lenzilumab Efficacy and Safety in Newly Hospitalized COVID-19 Subjects: Results from the LIVE-AIR Phase 3 Randomized Double-Blind Placebo-Controlled Trial. medRxiv 2021. [Preprint]
Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)
