Bactericidal/permeability-increasing protein [rBPI(21)] in patients with hemorrhage due to trauma: Results of a multicenter phase II clinical trial

Background: Infection and organ failure are the most common causes of death or serious complication in trauma patients surviving initial resuscitation and operation, Of the many possible causes of these complications, bacteri al translocation and release of harmful cytokines and oxygen free radicals may play an important role in the pathogenesis of the complications associa ted with traumatic hemorrhage. Recombinant human bactericidal/permeability- increasing protein (rBPI(21)) has antibacterial and antiendotoxin propertie s, reduces cytokine levels, and increases survival in animal models of hemo rrhagic shock. The primary objective of this study was to evaluate the safe ty and efficacy of prophylactic rBPI(21) infusion in patients with hemorrha ge due to trauma. Methods: This was a phase II, multicenter, randomized, double-blind, placeb o-controlled trial, Patients who required at least 2 U of blood were random ized to receive rBPI(21) (4 mg . kg(-1) . d(-1) for 2 consecutive days) or an equivalent volume of placebo by continuous infusion within 12 hours of i njury, The primary efficacy end point was mortality or serious complication occurring during the first 15 days of the study, Safety was monitored clin ically and by laboratory panels during the study period. Results: A total of 401 patients were treated (202 in the rBPI(21) group an d 199 in the placebo group). The composite end point rate of mortality or s erious complication through day 15 was 46% in the placebo group and 39% in the rBPI(21) group (hazard ratio = 0.79; p = 0.13). Secondary analysis, whi ch adjusted for age, mechanism of injury, Injury Severity Score (1990 versi on), and units of blood received before study drug infusion showed similar results (hazard ratio = 0.79; p = 0.14). The proportion of patients who dev eloped at least one serious organ dysfunction was 22% in the placebo group and 16% in the rBPI(21) group (hazard ratio = 0.71; p = 0.14). The proporti on of patients who developed either pneumonia or acute respiratory distress syndrome was 32% in the placebo group and 22% in the rBPI(21) group (hazar d ratio = 0.66; post hoc p = 0.03). The beneficial trends of rBPI(21) were observed in both blunt and penetrating trauma and were generally observed a cross different age groups, Injury Severity Scores, and units of blood tran sfused. No treatment difference was observed in mortality or resource utili zation in this phase II study, Conclusion: rBPI(21) was well-tolerated and demonstrated a favorable trend in reducing the composite primary end point of mortality or serious complic ation through day 15, especially respiratory complications, in patients wit h hemorrhage due to trauma. A phase III study is currently in progress.