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*

ObjectiveIn 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. DesignBlinded, critical, integrated review of data. SettingParticipating sites. PatientsThe 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. InterventionsWe 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 ResultsThe 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. ConclusionsThe 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.

[1]  Thomas R. Riley,et al.  A Randomized Double-blind Placebo-controlled Trial , 2004 .

[2]  Rainald Fischer,et al.  Daily hemodialysis and the outcome of acute renal failure. , 2002, The New England journal of medicine.

[3]  E. Ivers,et al.  Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock , 2001 .

[4]  M Schetz,et al.  Intensive insulin therapy in critically ill patients. , 2001, The New England journal of medicine.

[5]  D. Moher,et al.  The Revised CONSORT Statement for Reporting Randomized Trials: Explanation and Elaboration , 2001, Annals of Internal Medicine.

[6]  J Ean,et al.  Efficacy and safety of recombinant human activated protein C for severe sepsis. , 2001, The New England journal of medicine.

[7]  R. Collins,et al.  Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials , 2001, The Lancet.

[8]  J. Dhainaut,et al.  Perspectives in Anti-Inflammatory Therapies in Sepsis , 2001 .

[9]  J. Pugin,et al.  Evolving Concepts in Sepsis and Septic Shock , 2001, Perspectives on Critical Care Infectious Diseases.

[10]  P. Sleight Debate: Subgroup analyses in clinical trials: fun to look at - but don't believe them! , 2000, Current controlled trials in cardiovascular medicine.

[11]  Rinaldo Bellomo,et al.  Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial , 2000, The Lancet.

[12]  G Sherman,et al.  Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. , 1999, Chest.

[13]  M. Schaller,et al.  Confirmatory platelet-activating factor receptor antagonist trial in patients with severe gram-negative bacterial sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. BN 52021 Sepsis Investigator Group. , 1998, Critical care medicine.

[14]  J. Bartlett,et al.  GUIDELINES FROM THE INFECTIOUS DISEASES SOCIETY OF AMERICA Community-Acquired Pneumonia in Adults: Guidelines for Management , 1998 .

[15]  J. Bartlett,et al.  Community-acquired pneumonia in adults: guidelines for management. The Infectious Diseases Society of America. , 1998, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[16]  R. Finch,et al.  Design of clinical trials in sepsis: problems and pitfalls. , 1998, The Journal of antimicrobial chemotherapy.

[17]  S. Opal,et al.  Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. , 1997, Critical care medicine.

[18]  C. Sprung,et al.  Influence of alterations in forgoing life-sustaining treatment practices on a clinical sepsis trial , 1997 .

[19]  C. Sprung,et al.  Influence of alterations in foregoing life-sustaining treatment practices on a clinical sepsis trial. The HA-1A Sepsis Study Group. , 1997, Critical care medicine.

[20]  M. Glauser,et al.  International sepsis trial (INTERSEPT): role and impact of a clinical evaluation committee. , 1996, Critical care medicine.

[21]  J. Carlet,et al.  INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. , 1996, Critical care medicine.

[22]  I. Olkin,et al.  Improving the quality of reporting of randomized controlled trials. The CONSORT statement. , 1996, JAMA.

[23]  R A Weinstein,et al.  Strategies to Prevent and Control the Emergence and Spread of Antimicrobial-Resistant Microorganisms in Hospitals. A challenge to hospital leadership. , 1996, JAMA.

[24]  Kenneth F. Schulz,et al.  The CONSORT Statement , 1996 .

[25]  G. Koch,et al.  Efficacy and Safety of Monoclonal Antibody to Human Tumor Necrosis Factor α in Patients With Sepsis Syndrome: A Randomized, Controlled, Double-blind, Multicenter Clinical Trial , 1995 .

[26]  S. Nasraway,et al.  Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. , 1995, JAMA.

[27]  J. Dhainaut,et al.  Platelet-activating factor antagonists as therapeutic strategy in sepsis. , 1994, Progress in clinical and biological research.

[28]  C. Sprung,et al.  Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. , 1991 .

[29]  E. Draper,et al.  APACHE II: A severity of disease classification system , 1985, Critical care medicine.

[30]  J. Enders,et al.  Infectious Diseases Society of America. , 1969, Antimicrobial agents and chemotherapy.