Drotrecogin Alfa (Activated) Treatment in Severe Sepsis From the Global Open-Label Trial ENHANCE: Further Evidence for Survival and Safety and Implications for Early Treatment

Jean-Louis Vincent, MD, PhD, FCCM; Gordon R. Bernard, MD; Richard Beale, MD; Christopher Doig, MD; Christian Putensen, MD, PhD; Jean-Francois Dhainaut, MD, PhD; Antonio Artigas, MD, PhD; Roberto Fumagalli, MD; William Macias, MD, PhD; Theressa Wright, MD; Kar Wong, PhD; David P. Sundin, PhD; Mary Ann Turlo, RN, MSc; Jonathan Janes, MRCP

Disclosures

Crit Care Med. 2005;33(10):2266-2277. 

In This Article

Abstract and Introduction

Objective: To provide further evidence for the efficacy and safety of drotrecogin alfa (activated) treatment in severe sepsis.
Design: Single-arm, open-label, trial of drotrecogin alfa (activated) treatment in severe sepsis patients. Enrollment began in March 2001 and day-28 follow-up completed in January 2003.
Setting: ENHANCE took place in 25 countries at 361 sites.
Patients: Patients with known or suspected infection, three or four systemic inflammatory response syndrome criteria, and one or more sepsis-induced organ dysfunctions. Of 2,434 adults entered, 2,378 received drotrecogin alfa (activated), and of these, 2,375 completed the protocol.
Interventions: Drotrecogin alfa (activated) was infused at a dose of 24 µg/kg/hr for 96 hrs.
Measurements and Main Results: The 28-day all-cause mortality approximated that observed in PROWESS (25.3% vs. 24.7%). Although patients in ENHANCE had increased serious bleeding rates compared with patients in the drotrecogin alfa (activated) arm of PROWESS (during infusion, 3.6% vs. 2.4%; postinfusion, 3.2% vs. 1.2%; 28-day, 6.5% vs. 3.5%), increased postinfusion bleeding suggested a higher background bleeding rate. Intracranial hemorrhage was more common in ENHANCE than PROWESS (during infusion, 0.6% vs. 0.2%; 28-day, 1.5% vs. 0.2%). The incidence of fatal intracranial hemorrhage was the same during infusion (0.2%) and higher at 28 days (0.5% vs. 0.2%). ENHANCE patients treated within 0-24 hrs from their first sepsis-induced organ dysfunction had lower observed mortality rate than those treated after 24 hrs (22.9% vs. 27.4%, p = .01).
Conclusions: ENHANCE provides supportive evidence for the favorable benefit/risk ratio observed in PROWESS and suggests that more effective use of drotrecogin alfa (activated) might be obtained by initiating therapy earlier.

Although there have been ongoing improvements in supportive care and antimicrobial therapies, severe sepsis remains a significant burden to health care systems and a serious cause of morbidity and mortality in the intensive care unit (ICU). In fact, the incidence of sepsis has continued to increase, with only minimal reduction in mortality rate despite these improvements.[1,2] Difficulties with consistent, early identification of severe sepsis and a lack of proven therapies have hampered efforts to improve outcomes. Recently, 11 societies have collaborated and endorsed a set of guidelines designed to improve patient outcome in sepsis.[3] In addition, drotrecogin alfa (activated) (DrotAA), a recombinant form of human activated protein C, has been approved in >50 countries for the treatment of severe sepsis patients at high risk of death or with multiple organ dysfunctions.

Approval of DrotAA for treatment of severe sepsis was based on Results of the PROWESS trial.[4] PROWESS was a double blind, placebo-controlled trial that enrolled 1,690 patients, randomly assigned to receive DrotAA (n = 850) or placebo (n = 840), in addition to standard care. At a predefined interim analysis, an independent data monitoring board recommended that the trial stop early due to the demonstrated efficacy. As the only compound approved for reduction of mortality from severe sepsis, subsequent trials designed to better understand severe sepsis and the mechanism of action of DrotAA became an ethical conundrum, particularly with regard to the use of a control group. To provide important supplementary safety and efficacy evaluation, ENHANCE was the vehicle chosen to provide this information and was designed as a global, open-label, single arm trial.

Although single-arm trials have the inherent problem of being unblinded and having no placebo control, they can provide important supplementary safety data as well as potential confirmatory efficacy data by reproducing an efficacy outcome similar to a phase III trial, in this case PROWESS. In addition, open-label trials can potentially provide a different aspect as to how a compound may be used in everyday clinical practice because they are predominantly performed in a wider sampling of hospitals outside the typical academic institution setting of a phase III trial.[5]

The underlying premise for the ENHANCE clinical trial was that DrotAA would have similar efficacy and safety in a setting more like normal clinical practice than that observed in the PROWESS clinical trial. The primary objectives of the ENHANCE trial were to provide additional safety and efficacy information concerning the use of DrotAA among patients with severe sepsis.

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