Project Summary/Abstract: Anti CD14 (CaTT) The SARS-CoV-2 pandemic continues to spread around the world, causing widespread illness with significant mortality, overburdening health care systems and disrupting the global economy. Severe illness is caused by viral infection of host cells leading to the generation of secondary inflammatory responses that cause serious organ injury. We propose to test a novel treatment that will add to antiviral therapy by blunting the host innate immune inflammatory response to virally infected host cells using IC14, a specific blocking monoclonal antibody to the CD14 pattern recognition receptor on macrophages, dendritic cells and other cells of the innate immune system. In combination with a primary antiviral drug (e.g. remdesivir), this treatment strategy should reduce host inflammatory responses and speed resolution of illness. The primary hypothesis is that inhibiting the CD14 pattern recognition receptor will reduce the intensity of deleterious host inflammatory responses to the SARS-CoV-2 virus and secondary tissue damage and improve outcomes in patients with COVID-19 illness. We will conduct a multicenter randomized controlled trial in 300 patients in 15 US clinical centers in order to determine the efficacy and safety of IC14 in patients hospitalized with respiratory disease due to SARS-CoV-2. In Aim 1 we will determine whether IC14 improves the time to resolution of disease using an eight-point ordinal scale. In Aim 2 we will determine whether IC14 reduces the need for high level respiratory support, including ICU care. In Aim 3 we will determine whether IC14 reduces the severity of systemic inflammation and the recovery of virus in nasal swabs. Overall, this program will determine whether treatment with IC14 is an effective new approach to lessen systemic inflammation and organ injury triggered by the SARS-CoV-2 virus and improves outcomes in patients hospitalized with COVID-19 illness.