Phase 3 Study to Evaluate Efficacy and Safety of Lenzilumab in Patients With COVID-19

Study Overview
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Brief Summary
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The primary objective of this study is to assess whether the use of lenzilumab in addition to current standard of care can alleviate the immune-mediated cytokine release syndrome (CRS) and improve ventilator-free survival in hospitalized subjects with severe or critical COVID-19 pneumonia.

Detailed Description
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In COVID-19, high levels of granulocyte macrophage-colony stimulating factor (GM-CSF) and inflammatory myeloid cells correlate with disease severity, cytokine storm, and respiratory failure. The mortality rate for hospitalized COVID-19 patients remains unacceptably high, particularly in patients who progress to invasive mechanical ventilation (IMV). This randomized, double-blind, multicenter, placebo-controlled pivotal phase 3 trial will evaluate the impact of lenzilumab (anti-human GM-CSF monoclonal antibody) on ventilator-free survival in hospitalized, hypoxic patients with COVID-19. The study is also designed to evaluate other key endpoints, including ventilator-free days, duration of ICU stay, incidence of IMV, ECMO and/or death, time to death, all-cause mortality and time to recovery. Approximately 516 patients will be randomized to receive lenzilumab + SOC vs. placebo + SOC in a 1:1 ratio.

Official Title
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A Phase 3 Randomized, Placebo-Controlled Study of Lenzilumab in Hospitalized Patients With Severe and Critical COVID-19 Pneumonia

Conditions
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Coronavirus Disease 2019 (COVID-19) Pneumonia

Intervention / Treatment
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* Biological: Lenzilumab
* Drug: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults 18 years of age or older who are capable of providing informed consent or have a proxy capable of giving consent for them Virologic confirmation of SARS-CoV-2 infection via any FDA authorized diagnostic test for SARS-CoV-2 Pneumonia diagnosed by Chest X-ray or Computed Tomography revealing infiltrates consistent with pneumonia SpO2 ≤ 94% on room air and/or require low-flow supplemental oxygen and/or require high-flow oxygen support or NIPPV Hospitalized, not requiring invasive mechanical ventilation during this hospitalization Have not participated in other clinical trial for COVID-19 using an immunomodulatory monoclonal antibody or kinase inhibitor (use of remdesivir, corticosteroids, convalescent plasma, hydroxychloroquine or chloroquine is permitted) Females of childbearing potential must have a negative serum or urine pregnancy test Exclusion Criteria: Requiring invasive mechanical ventilation or extracorporeal membrane oxygenation prior to randomization Confirmed diagnosis of bacterial pneumonia or other active/uncontrolled fungal or viral infections at screening/baseline Known active tuberculosis (TB), history of incompletely treated TB or suspected or known extrapulmonary TB Currently receiving treatment for hepatitis A, hepatitis B, hepatitis C or HIV infection History of pulmonary alveolar proteinosis (PAP) Women of childbearing potential who are pregnant or breastfeeding Known hypersensitivity to lenzilumab or any of its components Use of any FDA authorized anti-IL-6 (e.g., tocilizumab, sarilumab, sitlukimab), anti-IL-1 (e.g., anakinra, canakinumab), kinase inhibitor (e.g., baracitinib, ibrutinib, acalabrutinib), or neutralizing monoclonal antibody (e.g. bamlanivimab or casirivimab/imdevimab) therapy to treat COVID-19 within 8 weeks prior to randomization Use of GM-CSF agents (e.g., sargramostim) within prior 2 months of randomization Expected survival < 48h in the opinion of the investigator Any condition that, in the opinion of the investigator, is likely to interfere with the safety and efficacy of the study treatment or puts the patient at unacceptably high risk from the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenzilumab Arm<br>Participants will receive IV infusion of lenzilumab upon randomization at a pre-specified dosing interval and continued administration of standard of care | Biological: Lenzilumab<br>* Administered as an intravenous (IV) infusion<br>* Other names: Humaneered® anti-human GM-CSF monoclonal Antibody;Drug: Standard of Care<br>* Standard of care therapy can include remdesivir and/or dexamethasone per institutional treatment guidelines or written policies<br>|
| Placebo Comparator: Placebo Arm<br>Participants will receive IV infusion of preservative-free 0.9% sodium chloride solution upon randomization matched to lenzilumab at same pre-specified dosing interval and continued administration of standard of care | Drug: Standard of Care<br>* Standard of care therapy can include remdesivir and/or dexamethasone per institutional treatment guidelines or written policies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator-free Survival |  | Up to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator-free Days |  | Up to Day 28 | 
| Duration of Intensive Care Unit (ICU) Stay |  | Up to Day 28 | 
| Incidence of Invasive Mechanical Ventilation, ECMO and/or Death |  | Up to Day 28 | 
| Time to Death |  | Up to Day 28 | 
| All-cause Mortality |  | Day 28 | 
| Time to Recovery | Time to recovery is defined as the first day on which a subject satisfies one of the following 3 categories from the 8-point ordinal scale (Hospitalized, not requiring supplemental oxygen-no longer requires ongoing medical care; Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized, no limitations on activities). | Up to Day 28 | 
| Incidence of severe acute respiratory distress syndrome (ARDS) |  | Up to Day 28 | 
| Duration of Hospitalization |  | Up to Day 28 | 
| Time to Improvement in 1 or 2 Categories using 8-point Ordinal Scale |  | Up to Day 28 | 
| Number of Subjects Alive and Off Oxygen |  | Up to Day 60 | 
| Percentage of Participants Experiencing Adverse Events | Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | Up to Day 60 | 
| Percentage of Participants Experiencing Serious Adverse Events | Using the NCI CTCAE version 5.0 | Up to Day 60 | 
| Proportion of Subjects Discharged from Hospital |  | Up to Day 60 | 
| Time to improvement in oxygenation for > 48 hours |  | Up to Day 28 | 
| Incidence of Non-invasive Ventilation (or Use of High-flow Oxygen Device) |  | Up to Day 28 | 
| Time to Clinical Improvement, Defined as NEWS2 < 2 Maintained for 24 Hours | NEWS2 consists of: Physiological Parameters: respiration rate (per minute), SpO2 Scale 1 (%), SpO2 Scale 2 (%), use of air or oxygen, systolic blood pressure (mmHg), pulse (per minute), consciousness and temperature (°C) | Up to Day 28 | 
| Change from Baseline to Day 28 in Clinical status Based on the 8-point Ordinal Scale |  | Up to Day 28 | 
| Duration of Time on Low-flow or High-flow Supplemental Oxygen |  | Up to Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF), GM-CSF monoclonal antibody, Cytokine Release Syndrome (CRS), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Lenzilumab, Cytokine Storm