Drotrecogin alfa (activated) in adults with septic shock
The New England Journal of Medicine. 2012;366((22):):2055-64.
BACKGROUND There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 ?g per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.).
Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated)
Critical Care (London, England). 2010;14((6):):R229.
INTRODUCTION Serial alterations in protein C levels appear to correlate with disease severity in patients with severe sepsis, and it may be possible to tailor severe sepsis therapy with the use of this biomarker. The purpose of this study was to evaluate the dose and duration of drotrecogin alfa (activated) treatment using serial measurements of protein C compared to standard therapy in patients with severe sepsis. METHODS This was a phase 2 multicenter, randomized, double-blind, controlled study. Adult patients with two or more sepsis-induced organ dysfunctions were enrolled. Protein C deficient patients were randomized to standard therapy (24 μg/kg/hr infusion for 96 hours) or alternative therapy (higher dose and/or variable duration; 24/30/36 μg/kg/hr for 48 to 168 hours). The primary outcome was a change in protein C level in the alternative therapy group, between study Day 1 and Day 7, compared to standard therapy. RESULTS Of 557 patients enrolled, 433 patients received randomized therapy; 206 alternative, and 227 standard. Baseline characteristics of the groups were largely similar. The difference in absolute change in protein C from Day 1 to Day 7 between the two therapy groups was 7% (P = 0. 011). Higher doses and longer infusions were associated with a more pronounced increase in protein C level, with no serious bleeding events. The same doses and longer infusions were associated with a larger increase in protein C level; higher rates of serious bleeding when groups received the same treatment; but no clear increased risk of bleeding during the longer infusion. This group also experienced a higher mortality rate; however, there was no clear link to infusion duration. CONCLUSIONS The study met its primary objective of increased protein C levels in patients receiving alternative therapy demonstrating that variable doses and/or duration of drotrecogin alfa (activated) can improve protein C levels, and also provides valuable information for incorporation into potential future studies. TRIAL REGISTRATION ClinicalTrials. gov identifier: NCT00386425.
A multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial assessing safety and efficacy of active site inactivated recombinant factor VIIa in subjects with acute lung injury or acute respiratory distress syndrome
Critical Care Medicine. 2009;37((6):):1874-80.
OBJECTIVE To evaluate the safety and efficacy of active site inactivated recombinant factor VIIa (FFR-rFVIIa) in patients with acute respiratory distress syndrome. DESIGN Phase II, randomized, double-blind, placebo-controlled, dose-escalation trial. SETTING Forty-six intensive care units (ICU) in ten countries. PATIENTS All adult (>or=18 years), mechanically ventilated patients with acute onset (within 48 hour) of acute lung injury/acute respiratory distress syndrome were included. INTERVENTIONS Four sequential (in ascending order) treatment groups (cohorts) in single and multiple dosing strategies. Subjects were randomized in a 2:1 ratio to either FFR-rFVIIa or placebo within each cohort. MEASUREMENTS AND RESULTS Data were collected daily for 7 days and on days 14 and 28 for efficacy variables including hematology and coagulation parameters, plasma d-dimer levels, plasma interleukin-6 levels, vital signs, ventilator parameters, lung injury score, and Sequential Organ Failure Assessment score. The study was discontinued prematurely by the Safety Committee based on statistical analysis of the mortality in cohort 3 (4 x 400 microg/kg), which suggested that, after adjusting for prognostic covariates, 28-day mortality was significantly higher in this cohort than in the placebo group and time to death was significantly shorter. A total of 214 patients (147 male) were included in the trial, mean age 59 years (range, 24-85 years). Overall, there were no significant differences in mortality rates in treated and placebo patients (36/144 deaths FFR-rFVIIa, 15/70 placebo). There was no treatment effect of FFR-rFVIIa on vital signs, blood chemistry parameters, hematology parameters, or amount of transfusion products required. There was a trend to increased bleeding with increasing FFR-rFVIIa dose. CONCLUSION In this randomized double-blind, placebo- controlled, dose-escalation trial, FFR-rFVIIa had no beneficial effects on morbidity or outcome overall. The cohort of patients receiving 4 x 400 g/kg of FFR-rFVIIa had increased mortality rates compared with placebo-treated patients, and there was a trend to increased risk of serious bleeding with increasing doses.
Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial
Critical Care Medicine. 2003;31((3):):834-40.
OBJECTIVE To assess morbidity in patients with severe sepsis managed with and without drotrecogin alfa (activated). DESIGN Analysis of secondary end points in a prospective, randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (PROWESS). SETTING A total of 164 medical institutions in 11 countries. PATIENTS A total of 1,690 consecutive adult patients with severe sepsis. INTERVENTIONS A 96-hr infusion of drotrecogin alfa (activated) (human recombinant activated protein C) or placebo. MEASUREMENTS AND MAIN RESULTS Sequential Organ Failure Assessment (SOFA) scores for cardiovascular, respiratory, renal, hematologic, and hepatic organ systems were measured for 28 days. Mean cardiovascular SOFA scores were significantly lower for patients treated with drotrecogin alfa (activated) compared with placebo patients over this time period (p = . 022). Drotrecogin alfa (activated)-treated patients also showed significantly faster resolution of cardiovascular (p = . 009) and respiratory (p = . 009) dysfunction and significantly slower onset of hematologic organ dysfunction (p = . 041) compared with placebo patients for days 1 to 7. No significant differences in morbidity were observed between treatment groups among 28-day survivors. CONCLUSION Drotrecogin alfa (activated) demonstrated significant improvements in organ function compared with placebo in a large phase 3 clinical trial that has shown a mortality benefit in patients with severe sepsis.
Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial
Intensive Care Medicine. 2003;29((6):):894-903.
OBJECTIVE Based on the results of the PROWESS trial the European Agency for the Evaluation of Medicinal Products has recently approved drotrecogin alfa (activated) for treatment of adult patients with severe sepsis and multiple-organ failure. We report study's data on efficacy and safety in patients with multiple-organ dysfunction. DESIGN AND SETTING Randomized, double-blind, placebo-controlled, multicenter trial in 164 medical centers. PATIENTS 1271 patients (75. 2% of the intention-to-treat population, n=1690) with multiple-organ dysfunction at study entry. INTERVENTIONS Drotrecogin alfa (activated) n=634, 24 micro g/kg per hour for 96 h or placebo ( n=637). RESULTS Observed 28-day mortality was significantly lower with drug treatment than with placebo (26. 5%vs. 33. 9%), cardiovascular and respiratory organ dysfunction resolved more rapidly over the first 7 days, and serious bleeding events were more frequent (2. 4% vs. 1. 3%). CONCLUSIONS Treatment with drotrecogin alfa (activated) significantly reduced 28-day mortality and more quickly resolved cardiovascular and respiratory organ dysfunction. The difference in serious bleeding event rates may be clinically significant; however, the overall benefit-risk profile appears favorable.