Anti-Granulocyte-Macrophage Colony-Stimulating Factor Monoclonal Antibody Gimsilumab for COVID-19 Pneumonia A Randomized, Double-Blind, Placebo-controlled Trial
Gerard J Criner, Frederick M Lang, Robert L Gottlieb, Kusum S Mathews, Tisha S Wang, Todd W Rice, Deepu Madduri, Shashi Bellam, Robert Jeanfreau, Amy H Case, Marilyn K Glassberg, George Marshall Lyon, Kareem Ahmad, Robert Mendelson, J Michael Dimaio, Maryann P Tran, Cedric W Spak, Jamil A Abbasi, Steven G Davis, Shekhar Ghamande, Steven Shen, Lisa Sherman, M.D Simon Lowry, S L Trial
doi:10.1164/rccm.202108-1859OCon
Rationale: GM-CSF (granulocyte-macrophage colony-stimulating factor) has emerged as a promising target against the hyperactive host immune response associated with coronavirus disease . Objectives: We sought to investigate the efficacy and safety of gimsilumab, an anti-GM-CSF monoclonal antibody, for the treatment of hospitalized patients with elevated inflammatory markers and hypoxemia secondary to COVID-19. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial, BREATHE, at 21 locations in the United States. Patients were randomized 1:1 to receive two doses of intravenous gimsilumab or placebo 1 week apart. The primary endpoint was all-cause mortality rate at Day 43. Key secondary outcomes were ventilator-free survival rate, ventilator-free days, and time to hospital discharge. Enrollment was halted early for futility based on an interim analysis. Measurements and Main Results: Of the planned 270 patients, 225 were randomized and dosed; 44.9% of patients were Hispanic or Latino. The gimsilumab and placebo groups experienced an allcause mortality rate at Day 43 of 28.3% and 23.2%, respectively (adjusted difference = 5% vs. placebo; 95% confidence interval [26 to 17]; P = 0.377). Overall mortality rates at 24 weeks were similar across the treatment arms. The key secondary endpoints demonstrated no significant differences between groups. Despite the high background use of corticosteroids and anticoagulants, adverse events were generally balanced between treatment groups. Conclusions: Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. The utility of anti-GM-CSF therapy for COVID-19 remains unclear. Clinical trial registered with www.clinicaltrials.gov (NCT 04351243).
Author disclosures are available with the text of this article at www.atsjournals.org.
Acknowledgment: The authors thank the patients and caregivers for their participation in the BREATHE study. The authors thank all site investigators and staff for their support in conducting the study. The authors thank the contract research organization Parexel for its important role. The authors continue to be inspired by the courage and resilience of the medical community and society at large in the face of this global pandemic.
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