Phase 2 randomized open label adaptive platform clinical trial of the clinical and biological effects of IC14 treatment in patients with severe COVID-19

In I-SPY COVID, a Phase 2 randomized open label adaptive platform clinical trial, we examined the clinical efficacy of the anti-CD14 monoclonal antibody IC14 for patients with severe COVID-19 requiring high-level respiratory support. As detailed in the initial report of the first seven investigational agents, IC14 treatment did not satisfy the Bayesian criteria for a large clinical effect, but a trend towards decreased mortality with IC14 treatment was observed. In this dedicated report of the IC14 arm, we provide updated and complementary efficacy, safety, and biomarker analyses. Methods: We produced updated estimates for the posterior probability of hazard ratios for mortality and time-to-recovery meeting graduation/futility criteria after data audit. Second, we performed an exploratory sub-group analysis, testing whether participants with higher baseline presepsin levels had a beneficial effect of IC14 treatment on 28-day all-cause mortality using a Cox-proportional hazards model, adjusting for age, sex, and illness severity. We evaluated for imbalances in severe adverse events with IC14 treatment. Finally, we investigated whether IC14 treatment was associated with CD14-pathway biomarker quintiles and Acute Respiratory Distress Syndrome (ARDS)/COVID-19 biomarker quintiles on study days 3 and 7, using ordinal logistic regression adjusted for baseline biomarker quintiles, age, sex, and illness severity. Findings: 143 participants were randomized to receive IC14 (n=67) or standard care (controls) (n=76). More patients in the control arm required mechanical ventilation at baseline (IC14 N=4; Control N=14, p=0.021). No significant changes in the primary efficacy analyses were observed following the data audit. IC14 met futility criteria for time-to-recovery and did not meet graduation or futility criteria for mortality. In an exploratory sub-group analysis adjusted for age, sex, and illness severity, we found that IC14 treatment may be linked to a reduction in 28-day mortality amongst patients with baseline presepsin levels > the median cut-point (presepsin high (N=47): aHR: 0.33, 95% CI: 0.10-1.01, p-value=0.053; presepsin low (N=48): aHR: 0.73, 95% CI: 0.23-2.30, p-value=0.58). IC14 treatment increased plasma concentrations of sCD14, a pharmacodynamic effect. Exploratory biomarker analyses suggested IC14 treatment was associated with decreased odds of elevated day 3 plasma concentration quintiles for the following biomarkers: IL-8, RAGE, VEGF, and presepsin, and was associated with increased odds of elevated day 3 plasma concentration quintiles of TNF-. Interpretation: While IC14 treatment did not demonstrate a large clinical effect, a trend toward reduced mortality was observed. IC14 had on-target pharmacodynamic effects, and a baseline marker of CD14-pathway activity, presepsin, might identify patients more likely to respond to IC14 treatment. Further clinical research is warranted to determine if IC14 treatment can improve outcomes and whether presepsin-guided IC14 therapy is effective in severe COVID-19.