An Enrichment Strategy For Sepsis Clinical Trials.

introductionSelecting participants for research based on their risk is an enrichment strategy with potential for enhancing clinical trials in sepsis. Adult Septic Shock Information and Stratification (ASSIST) is a tool for estimating mortality risk that incorporates a panel of biomarkers, age, lactate, and chronic health status. We assessed the utility of ASSIST as an enrichment strategy in a clinical trial testing the efficacy of a polyclonal antitumor necrosis factor-α fragment antibody (AZD9773) in adults with severe sepsis or septic shock. We hypothesized that the effects of AZD9773 are dependent on baseline mortality risk, as estimated by ASSIST.

methodsThis was a post hoc analysis of a recently completed trial of 300 subjects, randomized to placebo, low-dose AZD9773, or high-dose AZD9773. The study's primary endpoint was number of ventilator-free days. There were 286 subjects with available plasma samples from study entry. We measured the ASSIST biomarkers and assigned each subject to low, intermediate, and high-risk strata based on their ASSIST mortality probability. To mirror the study's original statistical plan, we estimated the least squares mean ventilator-free days for each study arm within risk strata.

resultsThe effect of study arm within ASSIST-based risk strata was significant (P = 0.017). Within the low-risk group, there was an increase in ventilator-free days for both drug arms. Within the intermediate-risk group, there was an increase in ventilator-free days among those in the low-dose arm, but a decrease in the high-dose arm. Among high-risk patients, there was a decrease of ventilator-free days in both drug arms. Analogous associations were observed when modeling 28-day mortality.

conclusionsIn this study, a beneficial effect of AZD9773 might have been observed if the trial selected low to intermediate-risk patients. ASSIST has the potential to serve as an enrichment tool for sepsis clinical trials.