The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): Role, methodology, and results

Jean François Dhainaut, Pierre François Laterre, Steven P. LaRosa, Howard Levy, Gary E. Garber, Darell Heiselman, Gary T. Kinasewitz, R. Bruce Light, Peter Morris, Roland Schein, Jean Pierre Sollet, Becky M. Bates, Barbara G. Utterback, Dennis Maki

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Objective: In the multinational PROWESS trial, drotrecogin alfa (activated) significantly reduced mortality rate in patients with severe sepsis compared with placebo. The use of large multiple-center trials can potentially complicate interpretation of results in severe sepsis populations because of variability in medical attitudes and practices and the frequency of confounding events such as protocol violations. The objective of this study was to perform a blinded, critical, integrated review of data from the 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial using a Clinical Evaluation Committee. Design: Blinded, critical, integrated review of data. Setting: Participating sites. Patients: The 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. Interventions: We performed analyses of the optimal cohort, defined as patients who had full compliance with the protocol, had evidence of an infection, and received adequate anti-infective therapy. We also performed other analyses, including significant underlying disorders, life support measures, and causes of death. Measurements and Main Results: The optimal cohort of 81.4% of the intention-to-treat population [drotrecogin alfa (activated), n = 695; placebo, n = 680] had similar baseline severity of illness between the two groups, a similar pharmacodynamic effect, and a relative risk of death estimate consistent with that observed in the overall PROWESS trial (0.83, 95% confidence interval 0.69-0.99 vs. 0.806, 95% confidence interval 0.69-0.94). A beneficial effect of drotrecogin alfa (activated) similarly was observed in patients with significant underlying disorders (0.73, 95% confidence interval 0.57-0.93) who were more severely ill and had a higher percentage of patients forgoing life-sustaining therapy. In contrast with the original investigator determinations, a benefit associated with drotrecogin alfa (activated) treatment in urinary tract infection adjudicated by the Clinical Evaluation Committee was observed. Conclusions: The survival benefit associated with drotrecogin alfa (activated) use was consistent with the results of the overall trial regardless of whether patients met criteria of the optimal cohort or had a significant underlying disorder.

Original languageEnglish (US)
Pages (from-to)2291-2301
Number of pages11
JournalCritical care medicine
Volume31
Issue number9
DOIs
StatePublished - Sep 1 2003

Keywords

  • Activated protein C
  • Antibiotics
  • Clinical evaluation committee
  • Drotrecogin alfa (activated)
  • Recombinant proteins
  • Sepsis
  • Septic shock
  • Severe sepsis
  • Xigris

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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    Dhainaut, J. F., Laterre, P. F., LaRosa, S. P., Levy, H., Garber, G. E., Heiselman, D., Kinasewitz, G. T., Light, R. B., Morris, P., Schein, R., Sollet, J. P., Bates, B. M., Utterback, B. G., & Maki, D. (2003). The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): Role, methodology, and results. Critical care medicine, 31(9), 2291-2301. https://doi.org/10.1097/01.CCM.0000085089.88077.AF