Inclusion Criteria:

• Admitted to a hospital with symptoms suggestive of Coronavirus Disease 2019 (COVID-19) and requires ongoing medical care.
• Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
• Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
• Male or non-pregnant female adult ≥ 18 years of age at time of enrollment.
• Illness of any duration and has laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay (e.g., Nucleic Acid Amplification Test [NAAT], antigen test) in any respiratory specimen, or saliva 5 times the upper limit of normal.
• Illness of any duration, and requiring, just prior to randomization, supplemental oxygen (any flow), mechanical ventilation or ECMO (ordinal scale category 5, 6, or 7). 
• Women of childbearing potential must agree to either abstinence or use at least one acceptable method of contraception from time of screening through 5 months post study IP dosing.
  • Note: acceptable methods include barrier contraceptives (condoms or diaphragms) with spermicide, intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive pills, and surgical sterilization. 
• Agrees not to participate in another blinded clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID-19 through day 29. 

Exclusion Criteria:

• ALT or AST > 5 times the upper limit of normal. 
• Subjects with a low glomerular filtration rate (eGFR), specifically:
  • Subjects with a glomerular filtration rate (eGFR) 20-30 mL/min are excluded unless in the opinion of the principal investigator (PI), the potential benefit of participation outweighs the potential risk of study participation;
  • All subjects with a glomerular filtration rate (eGFR) < 20 mL/min (including hemodialysis and hemofiltration) are excluded.
• Pregnancy or breast feeding.
• Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours of enrollment.
• Allergy to any study medication.
• Received five or more doses of remdesivir prior to screening.
• Received two or more doses of > 60 mg of prednisone or equivalent in the 7 days prior to screening.
• Received small molecule tyrosine kinase inhibitors, including Janus kinase (JAK) inhibitors (e.g., baricitinib, ibrutinib, acalabrutinib, imatinib, gefitinib), in the 4 weeks prior to screening.
• Received monoclonal antibodies targeting cytokines (e.g., tumor necrosis factor (TNF) inhibitors, anti-IL-1 [e.g., anakinra, canakinumab], anti-IL-6 [e.g., tocilizumab, sarilumab, sitlukimab]), or T-cells (e.g., abatacept) in the 4 weeks prior to screening.
• Received monoclonal antibodies targeting B-cells (e.g., rituximab, and including any targeting multiple cell lines including B-cells) in the 3 months prior to screening.
• Received granulocyte-macrophage colony-stimulating factor (GM-CSF) agents (e.g., sargramostim) within 2 months prior to screening.
• Received other immunosuppressants in the 4 weeks prior to screening and in the judgement of the investigator, the risk of immunosuppression with lenzilumab is larger than the risk of Coronavirus Disease 2019 (COVID-19).
• Received any live vaccine in the 4 weeks prior to screening.
• Known active tuberculosis.
• Known history of Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) or untreated hepatitis C (HCV) infection.
• History of pulmonary alveolar proteinosis (PAP).
• Has a malignancy currently receiving immunosuppressive chemotherapy, immunodeficiency, uncontrolled opportunistic infection, or uncontrolled cirrhosis.
• Has a medical condition that could, in the judgment of the investigator, limit the interpretation and generalizability of trial results.
• Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
• Previous participation in an ACTIV-5/Big Effect Trial (BET).