Bactericidal/permeability-increasing protein (rBPI21) in patients with hemorrhage due to trauma

Results of a multicenter phase II clinical trial

Demetrios Demetriades, J. Stanley Smith, Lewis E. Jacobson, Michael Moncure, Joseph Minei, Betty J. Nelson, Patrick J. Scannon

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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, bacterial translocation and release of harmful cytokines and oxygen free radicals may play an important role in the pathogenesis of the complications associated with traumatic hemorrhage. Recombinant human bactericidal/permeability-increasing protein (rBPI21) has antibacterial and antiendotoxin properties, reduces cytokine levels, and increases survival in animal models of hemorrhagic shock. The primary objective of this study was to evaluate the safety and efficacy of prophylactic rBPI21 infusion in patients with hemorrhage due to trauma. Methods: This was a phase II, multicenter, randomized, double-blind, placebo-controlled trial. Patients who required at least 2 U of blood were randomized to receive rBPI21 (4 mg·kg-1·d-1 for 2 consecutive days) or an equivalent volume of placebo by continuous infusion within 12 hours of injury. The primary efficacy end point was mortality or serious complication occurring during the first 15 days of the study. Safety was monitored clinically and by laboratory panels during the study period. Results: A total of 401 patients were treated (202 in the rBPI21 group and 199 in the placebo group). The composite end point rate of mortality or serious complication through day 15 was 46% in the placebo group and 39% in the rBPI21 group (hazard ratio = 0.79; p = 0.13). Secondary analysis, which adjusted for age, mechanism of injury, Injury Severity Score (1990 version), and units of blood received before study drug infusion showed similar results (hazard ratio = 0.79; p = 0.14). The proportion of patients who developed at least one serious organ dysfunction was 22% in the placebo group and 16% in the rBPI21 group (hazard ratio = 0.71; p = 0.14). The proportion of patients who developed either pneumonia or acute respiratory distress syndrome was 32% in the placebo group and 22% in the rBPI21 group (hazard ratio = 0.66; post hoc p = 0.03). The beneficial trends of rBPI21 were observed in both blunt and penetrating trauma and were generally observed across different age groups, Injury Severity Scores, and units of blood transfused. No treatment difference was observed in mortality or resource utilization in this phase II study. Conclusion: rBPI21 was well-tolerated and demonstrated a favorable trend in reducing the composite primary end point of mortality or serious complication through day 15, especially respiratory complications, in patients with hemorrhage due to trauma. A phase III study is currently in progress.

Original languageEnglish (US)
Pages (from-to)667-677
Number of pages11
JournalJournal of Trauma - Injury, Infection and Critical Care
Volume46
Issue number4
StatePublished - Apr 1999

Fingerprint

Phase II Clinical Trials
Hemorrhage
Placebos
Wounds and Injuries
Injury Severity Score
Mortality
Cytokines
Bacterial Translocation
Safety
Hemorrhagic Shock
Adult Respiratory Distress Syndrome
bactericidal permeability increasing protein
Resuscitation
Free Radicals
Cause of Death
Reactive Oxygen Species
Pneumonia
Animal Models
Age Groups
Survival

Keywords

  • ARDS
  • Hemorrhage
  • Infection
  • Organ failure
  • Pneumonia
  • Recombinant bactericidal/permeability-increasing protein (rBPI)
  • Trauma

ASJC Scopus subject areas

  • Surgery

Cite this

Bactericidal/permeability-increasing protein (rBPI21) in patients with hemorrhage due to trauma : Results of a multicenter phase II clinical trial. / Demetriades, Demetrios; Smith, J. Stanley; Jacobson, Lewis E.; Moncure, Michael; Minei, Joseph; Nelson, Betty J.; Scannon, Patrick J.

In: Journal of Trauma - Injury, Infection and Critical Care, Vol. 46, No. 4, 04.1999, p. 667-677.

Research output: Contribution to journalArticle

Demetriades, Demetrios ; Smith, J. Stanley ; Jacobson, Lewis E. ; Moncure, Michael ; Minei, Joseph ; Nelson, Betty J. ; Scannon, Patrick J. / Bactericidal/permeability-increasing protein (rBPI21) in patients with hemorrhage due to trauma : Results of a multicenter phase II clinical trial. In: Journal of Trauma - Injury, Infection and Critical Care. 1999 ; Vol. 46, No. 4. pp. 667-677.
@article{2a4e1462616648609ba7d9c4d5471c5d,
title = "Bactericidal/permeability-increasing protein (rBPI21) in patients with hemorrhage due to trauma: Results of a multicenter phase II clinical trial",
abstract = "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, bacterial translocation and release of harmful cytokines and oxygen free radicals may play an important role in the pathogenesis of the complications associated with traumatic hemorrhage. Recombinant human bactericidal/permeability-increasing protein (rBPI21) has antibacterial and antiendotoxin properties, reduces cytokine levels, and increases survival in animal models of hemorrhagic shock. The primary objective of this study was to evaluate the safety and efficacy of prophylactic rBPI21 infusion in patients with hemorrhage due to trauma. Methods: This was a phase II, multicenter, randomized, double-blind, placebo-controlled trial. Patients who required at least 2 U of blood were randomized to receive rBPI21 (4 mg·kg-1·d-1 for 2 consecutive days) or an equivalent volume of placebo by continuous infusion within 12 hours of injury. The primary efficacy end point was mortality or serious complication occurring during the first 15 days of the study. Safety was monitored clinically and by laboratory panels during the study period. Results: A total of 401 patients were treated (202 in the rBPI21 group and 199 in the placebo group). The composite end point rate of mortality or serious complication through day 15 was 46{\%} in the placebo group and 39{\%} in the rBPI21 group (hazard ratio = 0.79; p = 0.13). Secondary analysis, which adjusted for age, mechanism of injury, Injury Severity Score (1990 version), and units of blood received before study drug infusion showed similar results (hazard ratio = 0.79; p = 0.14). The proportion of patients who developed at least one serious organ dysfunction was 22{\%} in the placebo group and 16{\%} in the rBPI21 group (hazard ratio = 0.71; p = 0.14). The proportion of patients who developed either pneumonia or acute respiratory distress syndrome was 32{\%} in the placebo group and 22{\%} in the rBPI21 group (hazard ratio = 0.66; post hoc p = 0.03). The beneficial trends of rBPI21 were observed in both blunt and penetrating trauma and were generally observed across different age groups, Injury Severity Scores, and units of blood transfused. No treatment difference was observed in mortality or resource utilization in this phase II study. Conclusion: rBPI21 was well-tolerated and demonstrated a favorable trend in reducing the composite primary end point of mortality or serious complication through day 15, especially respiratory complications, in patients with hemorrhage due to trauma. A phase III study is currently in progress.",
keywords = "ARDS, Hemorrhage, Infection, Organ failure, Pneumonia, Recombinant bactericidal/permeability-increasing protein (rBPI), Trauma",
author = "Demetrios Demetriades and Smith, {J. Stanley} and Jacobson, {Lewis E.} and Michael Moncure and Joseph Minei and Nelson, {Betty J.} and Scannon, {Patrick J.}",
year = "1999",
month = "4",
language = "English (US)",
volume = "46",
pages = "667--677",
journal = "Journal of Trauma and Acute Care Surgery",
issn = "2163-0755",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Bactericidal/permeability-increasing protein (rBPI21) in patients with hemorrhage due to trauma

T2 - Results of a multicenter phase II clinical trial

AU - Demetriades, Demetrios

AU - Smith, J. Stanley

AU - Jacobson, Lewis E.

AU - Moncure, Michael

AU - Minei, Joseph

AU - Nelson, Betty J.

AU - Scannon, Patrick J.

PY - 1999/4

Y1 - 1999/4

N2 - 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, bacterial translocation and release of harmful cytokines and oxygen free radicals may play an important role in the pathogenesis of the complications associated with traumatic hemorrhage. Recombinant human bactericidal/permeability-increasing protein (rBPI21) has antibacterial and antiendotoxin properties, reduces cytokine levels, and increases survival in animal models of hemorrhagic shock. The primary objective of this study was to evaluate the safety and efficacy of prophylactic rBPI21 infusion in patients with hemorrhage due to trauma. Methods: This was a phase II, multicenter, randomized, double-blind, placebo-controlled trial. Patients who required at least 2 U of blood were randomized to receive rBPI21 (4 mg·kg-1·d-1 for 2 consecutive days) or an equivalent volume of placebo by continuous infusion within 12 hours of injury. The primary efficacy end point was mortality or serious complication occurring during the first 15 days of the study. Safety was monitored clinically and by laboratory panels during the study period. Results: A total of 401 patients were treated (202 in the rBPI21 group and 199 in the placebo group). The composite end point rate of mortality or serious complication through day 15 was 46% in the placebo group and 39% in the rBPI21 group (hazard ratio = 0.79; p = 0.13). Secondary analysis, which adjusted for age, mechanism of injury, Injury Severity Score (1990 version), and units of blood received before study drug infusion showed similar results (hazard ratio = 0.79; p = 0.14). The proportion of patients who developed at least one serious organ dysfunction was 22% in the placebo group and 16% in the rBPI21 group (hazard ratio = 0.71; p = 0.14). The proportion of patients who developed either pneumonia or acute respiratory distress syndrome was 32% in the placebo group and 22% in the rBPI21 group (hazard ratio = 0.66; post hoc p = 0.03). The beneficial trends of rBPI21 were observed in both blunt and penetrating trauma and were generally observed across different age groups, Injury Severity Scores, and units of blood transfused. No treatment difference was observed in mortality or resource utilization in this phase II study. Conclusion: rBPI21 was well-tolerated and demonstrated a favorable trend in reducing the composite primary end point of mortality or serious complication through day 15, especially respiratory complications, in patients with hemorrhage due to trauma. A phase III study is currently in progress.

AB - 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, bacterial translocation and release of harmful cytokines and oxygen free radicals may play an important role in the pathogenesis of the complications associated with traumatic hemorrhage. Recombinant human bactericidal/permeability-increasing protein (rBPI21) has antibacterial and antiendotoxin properties, reduces cytokine levels, and increases survival in animal models of hemorrhagic shock. The primary objective of this study was to evaluate the safety and efficacy of prophylactic rBPI21 infusion in patients with hemorrhage due to trauma. Methods: This was a phase II, multicenter, randomized, double-blind, placebo-controlled trial. Patients who required at least 2 U of blood were randomized to receive rBPI21 (4 mg·kg-1·d-1 for 2 consecutive days) or an equivalent volume of placebo by continuous infusion within 12 hours of injury. The primary efficacy end point was mortality or serious complication occurring during the first 15 days of the study. Safety was monitored clinically and by laboratory panels during the study period. Results: A total of 401 patients were treated (202 in the rBPI21 group and 199 in the placebo group). The composite end point rate of mortality or serious complication through day 15 was 46% in the placebo group and 39% in the rBPI21 group (hazard ratio = 0.79; p = 0.13). Secondary analysis, which adjusted for age, mechanism of injury, Injury Severity Score (1990 version), and units of blood received before study drug infusion showed similar results (hazard ratio = 0.79; p = 0.14). The proportion of patients who developed at least one serious organ dysfunction was 22% in the placebo group and 16% in the rBPI21 group (hazard ratio = 0.71; p = 0.14). The proportion of patients who developed either pneumonia or acute respiratory distress syndrome was 32% in the placebo group and 22% in the rBPI21 group (hazard ratio = 0.66; post hoc p = 0.03). The beneficial trends of rBPI21 were observed in both blunt and penetrating trauma and were generally observed across different age groups, Injury Severity Scores, and units of blood transfused. No treatment difference was observed in mortality or resource utilization in this phase II study. Conclusion: rBPI21 was well-tolerated and demonstrated a favorable trend in reducing the composite primary end point of mortality or serious complication through day 15, especially respiratory complications, in patients with hemorrhage due to trauma. A phase III study is currently in progress.

KW - ARDS

KW - Hemorrhage

KW - Infection

KW - Organ failure

KW - Pneumonia

KW - Recombinant bactericidal/permeability-increasing protein (rBPI)

KW - Trauma

UR - http://www.scopus.com/inward/record.url?scp=0032941856&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032941856&partnerID=8YFLogxK

M3 - Article

VL - 46

SP - 667

EP - 677

JO - Journal of Trauma and Acute Care Surgery

JF - Journal of Trauma and Acute Care Surgery

SN - 2163-0755

IS - 4

ER -