Clinical trial NCT04351152: Phase 3 Study to Evaluate Efficacy and Safety of Lenzilumab in Patients With COVID-19
Official title: A Phase 3 Randomized, Placebo-Controlled Study of Lenzilumab in Hospitalized Patients With Severe and Critical COVID-19 Pneumonia
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Coronavirus Disease 2019 (COVID-19) Pneumonia
Keywords: 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
Lead sponsor: Humanigen, Inc.
Sponsor class: INDUSTRY
First posted: 2020-04-17
Enrollment: 520
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Ventilator-free Survival
timeFrame: Up to Day 28
Secondary outcomes:
measure: Ventilator-free Days
timeFrame: Up to Day 28
measure: Duration of Intensive Care Unit (ICU) Stay
timeFrame: Up to Day 28
measure: Incidence of Invasive Mechanical Ventilation, ECMO and/or Death
timeFrame: Up to Day 28
measure: Time to Death
timeFrame: Up to Day 28
measure: All-cause Mortality
timeFrame: Day 28
measure: Time to Recovery
timeFrame: Up to Day 28
measure: Incidence of severe acute respiratory distress syndrome (ARDS)
timeFrame: Up to Day 28
measure: Duration of Hospitalization
timeFrame: Up to Day 28
measure: Time to Improvement in 1 or 2 Categories using 8-point Ordinal Scale
timeFrame: Up to Day 28
measure: Number of Subjects Alive and Off Oxygen
timeFrame: Up to Day 60
measure: Percentage of Participants Experiencing Adverse Events
timeFrame: Up to Day 60
measure: Percentage of Participants Experiencing Serious Adverse Events
timeFrame: Up to Day 60
measure: Proportion of Subjects Discharged from Hospital
timeFrame: Up to Day 60
measure: Time to improvement in oxygenation for > 48 hours
timeFrame: Up to Day 28
measure: Incidence of Non-invasive Ventilation (or Use of High-flow Oxygen Device)
timeFrame: Up to Day 28
measure: Time to Clinical Improvement, Defined as NEWS2 < 2 Maintained for 24 Hours
timeFrame: Up to Day 28
measure: Change from Baseline to Day 28 in Clinical status Based on the 8-point Ordinal Scale
timeFrame: Up to Day 28
measure: Duration of Time on Low-flow or High-flow Supplemental Oxygen
timeFrame: Up to Day 28
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Los Angeles
country: United States
facility: University of Southern California (USC) Medical Center
state: California
city: Los Angeles
country: United States
facility: USC - Los Angeles County Medical Center
state: California
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Edgewood
country: United States
facility: St. Elizabeth Healthcare
state: Kentucky
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock
state: New Hampshire
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: Rockville Centre
country: United States
facility: Mercy Medical Center
state: New York
city: Charlotte
country: United States
facility: Atrium Health
state: North Carolina
city: Austin
country: United States
facility: St. David's Healthcare
state: Texas
city: Austin
country: United States
facility: St. David's North Austin Medical Center
state: Texas
city: Dallas
country: United States
facility: Texas Health
state: Texas
city: Belo Horizonte
country: Brazil
facility: Hospital Vera Cruz
state: Minas Gerais
city: Natal
country: Brazil
facility: CPCLIN - Centro de Pesquisas Clínicas de Natal
state: Rio Grande Do Norte
city: Porto Alegre
country: Brazil
facility: Hospital São Lucas - PUCRS
state: Rio Grande Do Sul
city: Criciúma
country: Brazil
facility: Sociedade Literaria e Caritativa Santo Agostinho
state: Santa Catarina
city: Blumenau
country: Brazil
facility: Hospital Dia do Pulmão
state: São Paulo
city: Santos
country: Brazil
facility: Hospital Guilherme Alvaro
state: São Paulo
city: Sorocaba
country: Brazil
facility: Clinica de Alergia Martti Antila S/S LTDA
state: São Paulo
city: São Bernardo do Campo
country: Brazil
facility: CEMEC - Centro Multidisciplinar de Estudos Clínicos LTDA-EPP
state: São Paulo
city: São Paulo
country: Brazil
facility: Escola Paulista de Medicina (UNIFESP)
city: São Paulo
country: Brazil
facility: Hospital Heliópolis
city: São Paulo
country: Brazil
facility: Hospital São Luiz do Jabaquara/IDOR
Study officials:
affiliation: Humanigen, Inc.
name: Cameron Durrant, MD
role: STUDY_DIRECTOR
References:
citation: Temesgen Z, Kelley CF, Cerasoli F, Kilcoyne A, Chappell D, Durrant C, Ahmed O, Chappell G, Catterson V, Polk C, Badley A, Marconi VC; LIVE-AIR Study Group. C reactive protein utilisation, a biomarker for early COVID-19 treatment, improves lenzilumab efficacy: results from the randomised phase 3 'LIVE-AIR' trial. Thorax. 2023 Jun;78(6):606-616. doi: 10.1136/thoraxjnl-2022-218744. Epub 2022 Jul 6.
citation: Temesgen Z, Burger CD, Baker J, Polk C, Libertin CR, Kelley CF, Marconi VC, Orenstein R, Catterson VM, Aronstein WS, Durrant C, Chappell D, Ahmed O, Chappell G, Badley AD; LIVE-AIR Study Group. Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial. Lancet Respir Med. 2022 Mar;10(3):237-246. doi: 10.1016/S2213-2600(21)00494-X. Epub 2021 Dec 1.
citation: Temesgen Z, Burger CD, Baker J, Polk C, Libertin C, Kelley C, Marconi VC, Orenstein R, Durrant C, Chappell D, Ahmed O, Chappell G, Badley AD. LENZILUMAB EFFICACY AND SAFETY IN NEWLY HOSPITALIZED COVID-19 SUBJECTS: RESULTS FROM THE LIVE-AIR PHASE 3 RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL. medRxiv [Preprint]. 2021 May 5:2021.05.01.21256470. doi: 10.1101/2021.05.01.21256470.
citation: Aroldi A, Chiarle R, Gambacorti-Passerini C. Clinical Benefit of Lenzilumab in Cases of Coronavirus Disease 2019. Mayo Clin Proc. 2021 Mar;96(3):817. doi: 10.1016/j.mayocp.2020.12.030. Epub 2021 Jan 11. No abstract available.
citation: Temesgen Z, Assi M, Shweta FNU, Vergidis P, Rizza SA, Bauer PR, Pickering BW, Razonable RR, Libertin CR, Burger CD, Orenstein R, Vargas HE, Palraj R, Dababneh AS, Chappell G, Chappell D, Ahmed O, Sakemura R, Durrant C, Kenderian SS, Badley AD. GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia: A Case-Cohort Study. Mayo Clin Proc. 2020 Nov;95(11):2382-2394. doi: 10.1016/j.mayocp.2020.08.038. Epub 2020 Sep 3.