Abstract
BACKGROUND: Sepsis remains one of the most prevalent conditions necessitating admission to intensive care units and is associated with high mortality. Unfortunately, randomized trials examining therapeutics for critically-ill patients with sepsis have been disproportionately negative, failing to identify effective interventions, likely due to the dilution of treatment effects across highly diverse populations. Designing trials to identify patients that are most likely to benefit from an intervention based on biologic mechanism, known as predictive enrichment, may be an effective strategy for enhancing clinical trial efficacy. We conducted a systematic review to summarize the use of biological markers (biomarkers) used for predictive enrichment in randomized controlled trials (RCTs) including patients with sepsis. METHODS: We conducted this review following PRISMA-ScR guidelines. We searched OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials databases. We included RCTs that enrolled adult patients with sepsis that used molecular biomarkers for predictive enrichment in their study design. We summarize study characteristics, biomarkers used, predictive enrichment strategies, and trial outcomes narratively without statistical pooling. Risk of bias of individual studies was assessed using the Cochrane Risk of Bias tool. RESULTS: Of the 1,718 citations found with the search, we included 12 eligible studies. All studies used either blood-based circulating proteins or lipopolysaccharide markers for predictive enrichment. Five studies (42%) reported statistically significant impacts on the primary outcome, with three showing patient-important benefit (reduced mortality or disease severity) and two demonstrating improvements in surrogate outcomes related to biomarkers. Interventions that demonstrated benefit included immune, antimicrobial or coagulation modulating therapies. These five trials that showed benefit used suPAR, AT, mHLA-DR, IL-6 and EAA as biomarkers for predictive enrichment. CONCLUSIONS: This review characterizes the use of biomarkers for predictive enrichment in randomized trials of critically-ill patients with sepsis. Although the studies were heterogeneous in design and limited in number, those that employed biomarker-based enrichment strategies demonstrate a promising signal for enhanced clinical trial efficiency. The use of biomarkers for predictive enrichment in critical care trial design requires further exploration, investigation and validation.