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Clinical trial design and outcomes in patients with severe sepsis
1Medicine Infectious Disease Division, Brown University School of Medicine, Pawtucket, Rhode Island 02860, USA. steven_opal@brown.edu
Abstract:
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.
Insights
Designing clinical trials for severe sepsis is challenging due to disease complexity and patient heterogeneity. This review examines these difficulties and discusses past trial outcomes, including the FDA-approved therapy drotrecogin alfa (activated).
Area of Science:
- Critical Care Medicine
- Clinical Trial Design
- Sepsis Pathophysiology
Background:
- Severe sepsis is a prevalent, life-threatening, and costly condition.
- Numerous clinical trials for severe sepsis treatments have yielded negative results, highlighting challenges in trial design and patient selection.
- The complex interplay of inflammation and coagulation in severe sepsis complicates therapeutic development.
Purpose of the Study:
- To review the complex nature of sepsis and the inherent difficulties in conducting clinical trials for its management.
- To analyze factors contributing to the failure of investigational agents in severe sepsis trials.
- To discuss positive trial outcomes and propose a model for future severe sepsis clinical trials.
Main Methods:
- Review of existing literature on severe sepsis pathogenesis and clinical trial outcomes.
- Analysis of challenges in evaluating investigational agents, including animal model limitations and patient heterogeneity.
- Detailed discussion of the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial for drotrecogin alfa (activated).
Main Results:
- Multiple severe sepsis treatment trials have failed due to factors like disease heterogeneity and poor model correlation.
- Steroids, intensive insulin therapy, and activated protein C (drotrecogin alfa [activated]) have shown positive results in specific contexts.
- The PROWESS trial provides a potential model for successful severe sepsis clinical trial design.
Conclusions:
- Effective clinical trial design for severe sepsis requires addressing patient heterogeneity and complex pathophysiology.
- Understanding past trial failures and successes, like with drotrecogin alfa (activated), is crucial for future research.
- The PROWESS trial offers valuable insights for developing a robust model for future severe sepsis therapeutic evaluations.
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