Efficacy and safety of iloprost in patients with septic shock-induced endotheliopathy-Protocol for the multicenter randomized, placebo-controlled, blinded, investigator-initiated trial

Abstract

Background: In Europe 700.000 new cases of sepsis occur annually and more than 100.000 of these patients die due to multiorgan failure (MOF). We have identified shock-induced endotheliopathy (SHINE) to be associated with development of MOF and mortality. Furthermore, in patients with septic shock those with circulating levels of thrombomodulin (TM) above 10 ng/mL have twice the mortality (56% vs 28%) than those with levels below this level. Pilot studies indicate that infusion of iloprost (1 ng/kg/min) is associated with improved endothelial function in patients with septic shock.

Material and methods: This is a multicenter, randomized, blinded, investigator-initiated, adaptive phase 2B trial in up to 384 patients with septic shock-induced endotheliopathy defined by TM > 10 ng/mL who are allocated 1:1 to 72 hours continuous infusion of iloprost 1 ng/kg/min or placebo (equal volume of saline). The primary outcome is the mean daily modified Sequential Organ Failure Assessment (SOFA) score in the ICU up to day 90. Secondary outcomes include 28- and 90-day all-cause mortality, days alive without vasopressor in the ICU within 90 days, days alive without mechanical ventilation in the ICU within 90 days, days alive without renal replacement therapy in the ICU within 90 days, numbers of serious adverse reactions, and the number of serious adverse events within the first 7 days.

Discussion: This trial tests the safety and efficacy of iloprost vs placebo for 72 hours in patients with septic shock and SHINE. The outcome measures focus on the potential effect of the intervention to mitigate organ failure.

Trial registration: COMBAT-SHINE trial-EudraCT no. 2019-001131-31-Clinicaltrials.gov: NCT04123444-Ethics Committee no. H-19018258.

Keywords: clinical trial; iloprost; septic shock-induced endotheliopathy; thrombomodulin.