In the pivotal PROWESS trial, treatment with drotrecogin alfa (activated) [DrotAA] improved survival and had a favorable benefit-risk profile compared to placebo in adult patients with severe sepsis receiving standard supportive care. A global open-label trial of DrotAA in severe sepsis, ENHANCE, has recently been completed. Reported are 28-day mortality and safety-related observations during the study drug infusion period. Results are compared to PROWESS.
Inclusion/exclusion criteria and the definition of serious adverse events (SAE) were virtually identical to PROWESS. SAE bleeding rates, including intracranial hemorrhage (ICH), during the study drug infusion period (4 days infusion + 1 day) was determined and all-cause mortality assessed at day 28.
There were 2378 adult patients enrolled at 400 sites in 25 countries.The majority of SAE bleeding events were adjudicated as being procedure related. The ICH rate during infusion was 0.6% (n=15) of which 5 (0.2%) were fatal. Meningitis or platelets < 40,000/mm3 were present in 5/15 (33%) and 4/15 (27%) of ICH cases, respectively. Meningitis and/or platelets <40,000/mm3 occurred in 8/15 (53%) patients. In comparison, placebo-treated and DrotAA-treated patients in PROWESS had ICH rates of 0% and 0.2% (n=2), of which both were fatal.CONCLUSIONS: Overall 28-day mortality was similar between ENHANCE and the DrotAA arm of PROWESS. The SAE bleeding rate was numerically greater in ENHANCE than in PROWESS with many events being considered procedure related. The ICH rate during infusion was 0.6%. Consistent with previous reports, meningitis and severe thrombocytopenia are potential risk factors. The favorable benefit-risk profile observed in the DrotAA treated subjects of PROWESS is reinforced by the data from Global ENHANCE.
Results of the Global ENHANCE trial provide further support for the favorable benefit-risk ratio observed in the PROWESS trial.
Global ENHANCE (DrotAA) (n = 2378)PROWESS (DrotAA) (n = 850)PROWESS (Placebo) (n = 840)28-Day mortality25.3% (n=600)24.7% (n=210)30.8% (n=259)SAE bleeding rate during infusion period3.8% (n=91)2.4% (n=20)1.0% (n=8)
R. Beale, None. Eli Lilly and Company (Indianapolis, IN) provided support for this research.