Clinical trial design and outcomes in patients with severe sepsis.

Severe sepsis is common, frequently fatal, and expensive. Many factors related to the pathogenesis of severe sepsis have made it difficult to effectively design clinical trials for the management of this disease. Hence, multiple trials of compounds for the treatment of severe sepsis have yielded largely negative results, except in small subsets of patients. This review provides a synopsis of the complex nature of sepsis and the problems associated with sepsis trials. Emphasis is placed on the difficulties in evaluating investigational agents in patients with severe sepsis because of the heterogeneity of the disorder, lack of correlation between animal and human models, the complexity of the insult and the host reaction, and the interaction between inflammation and coagulation in severe sepsis. Additionally, positive results from trials of steroids, intensive insulin therapy, and activated protein C (drotrecogin alfa [activated]) will be discussed. Because drotrecogin alfa (activated) is the only Food and Drug Administration-approved therapy for severe sepsis, the Phase 3 Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial results will be discussed in detail to help define a model for further clinical trials on severe sepsis.