Success or Failure in Phase III Sepsis Trials : Comparisons between the Drotrecogin Alfa ( Activated ) and Antithrombin III Clinical Trials

The successful conclusion of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial of drotrecogin alfa (activated) — the official generic nomenclature for recombinant human Activated Protein C — in severe sepsis represents a long awaited milestone in clinical sepsis research [1]. This multinational Phase III trial successfully achieved a statistically significant reduction in 28-day all-cause mortality in an intention-to-treat analysis, when comparing the drotrecogin alfa (activated) group with the placebo control group. Eligible patients received either drotrecogin alfa (activated) administered by continuous infusion at a dose of 24 μg/kg/h for 4 days, or placebo. The mortality rate in those patients randomized to the drotrecogin alfa (activated) group (n=850) was 24.7%, while patients in the control group (n=840) had a mortality rate of 30.8% (p=0.005). This indicates an absolute reduction in mortality rate of 6.1% and a relative risk reduction (RRR) of 19.4% associated with drotrecogin alfa (activated) treatment. These results are a welcome departure from the almost uniformly disappointing outcomes from a myriad of other recent, randomized clinical trials for severe sepsis. Over the past 15 years, more than 20 similarly designed, multicenter sepsis trials with other agents have failed to demonstrate a statistically significant reduction in overall mortality [2,3]. It is worth noting that in three such clinical trials (tumor necrosis factor (p75):Fc fusion peptide [4], nitric oxide synthase inhibitor [5], and growth hormone [6]), patients randomized to the treatment groups actually experienced significantly higher mortality rates (p<0.01) than the placebo control groups. The highly favorable results observed in the PROWESS trial have not been seen in sepsis trials since the original Ziegler study with Escherichia coli J5 antisera for the treatment of Gram-negative bacteremia, almost 20 years ago [7]. Despite major advances in the understanding of the molecular pathogenesis of sepsis, it The success of the Phase III Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial of drotrecogin alfa (activated) in the treatment of severe sepsis provides an opportunity to contrast this experience with similar, yet unsuccessful, sepsis trials. The KyberSept multicenter trial of antithrombin III for severe sepsis was a contemporaneous study, which was compared with the PROWESS trial. An analysis of trial designs, population differences, and study endpoints may affect how future clinical trials are developed and conducted, and may account, in part, for the success of the PROWESS trial and the failure of the KyberSept trial to reach the primary endpoint of reduced mortality in severe sepsis. This review is an examination of both the final clinical trial reports from the KyberSept and PROWESS trials, provided in published abstracts, papers, and meeting reports, and supporting preclinical and clinical evidence published over the past 20 years. While both these highly visible clinical trials used endogenous anticoagulants that down-regulate the generation of thrombin in vivo, important differences exist in their anti-inflammatory properties, safety profiles, and antithrombotic mechanisms.