Anti-CD14 Treatment in Patients With Severe COVID-19 Clinical and Biological Effects in a Phase 2 Randomized Open-Label Adaptive Platform Clinical Trial

Background

Cluster of differentiation 14 (CD14)-dependent innate immunity contributes to poor outcomes in COVID-19 pneumonia.

Research Question

What are the clinical and biological effects of a blocking anti-CD14 monoclonal antibody (IC14) for treatment of severe COVID-19 pneumonia and what is the usefulness of a biomarker of CD14 pathway activation in predicting outcome?

Study Design And Methods

We report a preplanned secondary analysis of the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis to Coronavirus Disease of 2019 (I-SPY COVID) trial, which enrolled hospitalized patients with severe COVID-19 pneumonia who required high-level respiratory support at 19 medical centers in the United States. Participants were randomized to receive either IV IC14 (4 mg/kg on day 1, then 2 mg/kg on days 2-4; n = 67) or standard care (n = 76). Primary end points included time to recovery, defined as the first 2-day period with ≤ 6 L/min of oxygen, and mortality. In predefined secondary analyses, we tested the association between IC14 treatment and mortality in patients with high or low baseline plasma presepsin, a biomarker of CD14 pathway activity, and the effects of IC14 on plasma biomarkers of pharmacodynamics, injury, and inflammation.

Results

IC14 treatment did not improve time to recovery or 28-day mortality in the overall population, and the trial was stopped because of meeting futility criteria for the time-to-recovery end point. However, a predefined subgroup analysis showed that IC14 treatment was associated with a numerical reduction in 28-day mortality in participants with high (above median) baseline presepsin levels (n = 47; hazard ratio for mortality [HRm], 0.52; 95% credible interval, 0.22-1.22; posterior probability [Pr] HRm < 1 (Pr(HRm < 1 | data)) = 0.93). IC14 treatment increased plasma sCD14, a pharmacodynamic marker, and decreased plasma inflammatory biomarkers, including IL-8, receptor for advanced glycation end products, vascular endothelial growth factor, and presepsin.

Interpretation

Although IC14 treatment did not improve overall clinical outcomes, this new secondary analysis showed that IC14 produced the expected pharmacodynamic and biological effects and that baseline plasma presepsin concentrations may identify patients likely to respond to IC14 treatment. Further trials are needed to determine the efficacy of IC14 treatment in acute lung injury and the value of presepsin to identify patients most likely to respond.

Clinical Trial Registry

ClinicalTrials.gov; No.: NCT04488081; URL: www.clinicaltrials.gov