Phase 2, randomized, double-blind, placebo-controlled multi-center trial of the clinical and biological effects of anti-CD14 treatment in hospitalized patients with COVID-19 pneumoniaResearch in context
F. Linzee Mabrey,
Hui Nian,
Chang Yu,
Elizabeth M. Barnes,
Uma Malhotra,
Carmen Mikacenic,
Julia Goldstein,
D. Shane O'Mahony,
Julia Garcia-Diaz,
Patricia Finn,
Kirk Voelker,
Eric D. Morrell,
Wesley H. Self,
Patrice M. Becker,
Thomas R. Martin,
Mark M. Wurfel
Affiliations
F. Linzee Mabrey
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
Hui Nian
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
Chang Yu
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
Elizabeth M. Barnes
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
Uma Malhotra
Benaroya Research Institute at Virginia Mason, Seattle, WA, USA; Virginia Mason Franciscan Health, Seattle, WA, USA
Carmen Mikacenic
Benaroya Research Institute at Virginia Mason, Seattle, WA, USA; Virginia Mason Franciscan Health, Seattle, WA, USA
Julia Goldstein
National Institute of Allergy and Infectious Diseases, National Institute of Health, USA
D. Shane O'Mahony
Swedish Center for Research and Innovation, Swedish Medical Center, Seattle, WA, USA
Julia Garcia-Diaz
Ochsner Medical Center, New Orleans, LA, USA
Patricia Finn
University of Illinois Hospital and Health Sciences System, University of Illinois College of Medicine, Chicago, IL, USA
Kirk Voelker
Sarasota Memorial Healthcare System, Sarasota, FL, USA
Eric D. Morrell
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
Wesley H. Self
Vanderbilt Institute for Clinical and Translational Research and Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Patrice M. Becker
National Institute of Allergy and Infectious Diseases, National Institute of Health, USA
Thomas R. Martin
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
Mark M. Wurfel
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA; Corresponding author. 325 9th Avenue, BOX 359640, Harborview R&T Building Rm 606, Seattle, WA 98104, USA.
Summary: Background: Severe COVID-19 is associated with innate immunopathology, and CD14, a proximal activator of innate immunity, has been suggested as a potential therapeutic target. Methods: We conducted the COVID-19 anti-CD14 Treatment Trial (CaTT), a Phase II randomized, double-blind, placebo-controlled trial at 5 US-sites between April 12, 2021 and November 30, 2021 (NCT04391309). Hospitalized adults with COVID-19 requiring supplemental oxygen (<30 LPM) were randomized 1:1 to receive 4 daily doses of intravenous IC14, an anti-CD14 monoclonal antibody, or placebo. All participants received remdesivir. The primary outcome was time-to-resolution of illness, defined as improvement on the 8-point NIH-Ordinal COVID-19 Scale to category ≤3. Secondary endpoints were safety and exploratory endpoints were pro-inflammatory and antiviral mediators in serum on days 0–5 & 7. The trial was stopped after 40 patients were randomized and treated due to slow enrollment. Findings: 40 participants were randomized and treated with IC14 (n = 20) or placebo (n = 20). The median time-to-recovery was 6 days (95% CI, 5–11) in the IC14 group vs. 5 days (95% CI, 4–10) in the Placebo group (recovery rate ratio: 0.77 (95% CI, 0.40, 1.48) (log-rank p = 0.435). The number of adverse events was similar in each group, and no IC14-attributable secondary infections occurred. In repeated-measures mixed-effects analyses, IC14 treatment increased serum sCD14 concentrations, an expected pharmacodynamic effect. Pre-planned, exploratory analyses suggested that IC14 treatment decreased the trajectories of circulating MIP-1β and TNF-α. Interpretation: IC14 treatment did not improve time-to-resolution of illness in hypoxemic patients with COVID-19 in this small trial. Results of exploratory analyses suggested IC14 had biologic effects that warrant future clinical investigation. Funding: National Institute of Allergy and Infectious Diseases.
