Recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) in traumatic hemorrhagic shock: Results of a phase II clinical trial

Peter M Rhee, J. Morris, R. Durham, C. Hauser, M. Cipolle, R. Wilson, F. Luchette, N. McSwain, R. Miller, P. B. Angood, M. Moncure

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background: Activated neutrophils have been shown to play a pivotal role in resuscitation injury after traumatic hemorrhagic shock. Blocking the adhesion of neutrophils with a recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) may reduce resuscitation injury but increase the risk of infection. This was a dose-finding phase II study to determine safety, pharmacokinetics, pharmacodynamics, and clinical outcome parameters for additional studies. Methods: This was a prospective, placebo-controlled, randomized (3:1), double-blind phase II trial enrolling 116 blunt and penetrating trauma patients from 14 trauma centers over a 9-month period. Patients with hypotension (blood pressure ≤90 mm Hg) from hemorrhagic shock were given a single intravenous dose of rhuMAb CD18 or placebo. The three doses tested were0.5, 1, and 2 mg/kg. The drug was administered within 4 hours of the hypotensive episode and no later than 6 hours from time of injury. Exclusion criteria included head injury resulting in Glasgow Coma Scale score less than 8 or a history of cardiopulmonary resuscitation in the trauma center. An independent Drug Safety and Monitoring Review Board periodically reviewed unblinded data for safety issues and to give approval for dose escalation. Results: Minor and major infection rates in rhuMAb CD18 groups were comparable to placebo. There war no evidence of antibody formation against rhuMAb CD18. Linear PK was observed within the dose range studied. Duration of neutrophil binding was dose-dependent, with 2 mg/kg resulting in greater than 90% neutrophil CD18 receptor saturation for approximately 48 hours. The mortality was 6.7% (2 of 30) in the placebo group, 4.8% (1 of 21) in the 0.5-mg/kg group, 8.5% (4 of 47) in the 1-mg/kg group, and 0% (0 of 18) in the 2-mg/kg group. The study was not powered for efficacy, and none of the efficacy variables demonstrated statistical significance. Favorable trends were seen in the 2-mg/kg group as compared with placebo in median intensive care unit length of stay (5 vs. 9 days) and median time on ventilator (34 vs. 72 hours). Conclusions: A single 2-mg/kg dose of rhuMAb CD18 maintains greater than 90% saturation of neutrophil CD18 receptors for approximately 48 hours in patients with traumatic hemorrhagic shock undergoing resuscitation. There was no trend toward increased infection. A larger trial is needed to demonstrate the Clinical efficacy of rhuMAb CD18, perhaps using more reliable endpoints.

Original languageEnglish (US)
Pages (from-to)611-620
Number of pages10
JournalJournal of Trauma
Volume49
Issue number4
StatePublished - 2000
Externally publishedYes

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Traumatic Shock
Antibodies, Monoclonal, Humanized
Phase II Clinical Trials
Hemorrhagic Shock
Neutrophils
Placebos
Resuscitation
Trauma Centers
Wounds and Injuries
Clinical Trials Data Monitoring Committees
Infection
Safety
Glasgow Coma Scale
Drug Monitoring
Cardiopulmonary Resuscitation
Mechanical Ventilators
Craniocerebral Trauma
Hypotension
Antibody Formation
Intensive Care Units

Keywords

  • Acute lung injury
  • Adult respiratory distress syndrome
  • Infection
  • Multiple organ dysfunction syndrome
  • Neutrophils
  • Pharmacodynamics
  • Pharmacokinetics
  • Safety

ASJC Scopus subject areas

  • Surgery

Cite this

Recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) in traumatic hemorrhagic shock : Results of a phase II clinical trial. / Rhee, Peter M; Morris, J.; Durham, R.; Hauser, C.; Cipolle, M.; Wilson, R.; Luchette, F.; McSwain, N.; Miller, R.; Angood, P. B.; Moncure, M.

In: Journal of Trauma, Vol. 49, No. 4, 2000, p. 611-620.

Research output: Contribution to journalArticle

Rhee, PM, Morris, J, Durham, R, Hauser, C, Cipolle, M, Wilson, R, Luchette, F, McSwain, N, Miller, R, Angood, PB & Moncure, M 2000, 'Recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) in traumatic hemorrhagic shock: Results of a phase II clinical trial', Journal of Trauma, vol. 49, no. 4, pp. 611-620.
Rhee, Peter M ; Morris, J. ; Durham, R. ; Hauser, C. ; Cipolle, M. ; Wilson, R. ; Luchette, F. ; McSwain, N. ; Miller, R. ; Angood, P. B. ; Moncure, M. / Recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) in traumatic hemorrhagic shock : Results of a phase II clinical trial. In: Journal of Trauma. 2000 ; Vol. 49, No. 4. pp. 611-620.
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abstract = "Background: Activated neutrophils have been shown to play a pivotal role in resuscitation injury after traumatic hemorrhagic shock. Blocking the adhesion of neutrophils with a recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) may reduce resuscitation injury but increase the risk of infection. This was a dose-finding phase II study to determine safety, pharmacokinetics, pharmacodynamics, and clinical outcome parameters for additional studies. Methods: This was a prospective, placebo-controlled, randomized (3:1), double-blind phase II trial enrolling 116 blunt and penetrating trauma patients from 14 trauma centers over a 9-month period. Patients with hypotension (blood pressure ≤90 mm Hg) from hemorrhagic shock were given a single intravenous dose of rhuMAb CD18 or placebo. The three doses tested were0.5, 1, and 2 mg/kg. The drug was administered within 4 hours of the hypotensive episode and no later than 6 hours from time of injury. Exclusion criteria included head injury resulting in Glasgow Coma Scale score less than 8 or a history of cardiopulmonary resuscitation in the trauma center. An independent Drug Safety and Monitoring Review Board periodically reviewed unblinded data for safety issues and to give approval for dose escalation. Results: Minor and major infection rates in rhuMAb CD18 groups were comparable to placebo. There war no evidence of antibody formation against rhuMAb CD18. Linear PK was observed within the dose range studied. Duration of neutrophil binding was dose-dependent, with 2 mg/kg resulting in greater than 90{\%} neutrophil CD18 receptor saturation for approximately 48 hours. The mortality was 6.7{\%} (2 of 30) in the placebo group, 4.8{\%} (1 of 21) in the 0.5-mg/kg group, 8.5{\%} (4 of 47) in the 1-mg/kg group, and 0{\%} (0 of 18) in the 2-mg/kg group. The study was not powered for efficacy, and none of the efficacy variables demonstrated statistical significance. Favorable trends were seen in the 2-mg/kg group as compared with placebo in median intensive care unit length of stay (5 vs. 9 days) and median time on ventilator (34 vs. 72 hours). Conclusions: A single 2-mg/kg dose of rhuMAb CD18 maintains greater than 90{\%} saturation of neutrophil CD18 receptors for approximately 48 hours in patients with traumatic hemorrhagic shock undergoing resuscitation. There was no trend toward increased infection. A larger trial is needed to demonstrate the Clinical efficacy of rhuMAb CD18, perhaps using more reliable endpoints.",
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author = "Rhee, {Peter M} and J. Morris and R. Durham and C. Hauser and M. Cipolle and R. Wilson and F. Luchette and N. McSwain and R. Miller and Angood, {P. B.} and M. Moncure",
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T1 - Recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) in traumatic hemorrhagic shock

T2 - Results of a phase II clinical trial

AU - Rhee, Peter M

AU - Morris, J.

AU - Durham, R.

AU - Hauser, C.

AU - Cipolle, M.

AU - Wilson, R.

AU - Luchette, F.

AU - McSwain, N.

AU - Miller, R.

AU - Angood, P. B.

AU - Moncure, M.

PY - 2000

Y1 - 2000

N2 - Background: Activated neutrophils have been shown to play a pivotal role in resuscitation injury after traumatic hemorrhagic shock. Blocking the adhesion of neutrophils with a recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) may reduce resuscitation injury but increase the risk of infection. This was a dose-finding phase II study to determine safety, pharmacokinetics, pharmacodynamics, and clinical outcome parameters for additional studies. Methods: This was a prospective, placebo-controlled, randomized (3:1), double-blind phase II trial enrolling 116 blunt and penetrating trauma patients from 14 trauma centers over a 9-month period. Patients with hypotension (blood pressure ≤90 mm Hg) from hemorrhagic shock were given a single intravenous dose of rhuMAb CD18 or placebo. The three doses tested were0.5, 1, and 2 mg/kg. The drug was administered within 4 hours of the hypotensive episode and no later than 6 hours from time of injury. Exclusion criteria included head injury resulting in Glasgow Coma Scale score less than 8 or a history of cardiopulmonary resuscitation in the trauma center. An independent Drug Safety and Monitoring Review Board periodically reviewed unblinded data for safety issues and to give approval for dose escalation. Results: Minor and major infection rates in rhuMAb CD18 groups were comparable to placebo. There war no evidence of antibody formation against rhuMAb CD18. Linear PK was observed within the dose range studied. Duration of neutrophil binding was dose-dependent, with 2 mg/kg resulting in greater than 90% neutrophil CD18 receptor saturation for approximately 48 hours. The mortality was 6.7% (2 of 30) in the placebo group, 4.8% (1 of 21) in the 0.5-mg/kg group, 8.5% (4 of 47) in the 1-mg/kg group, and 0% (0 of 18) in the 2-mg/kg group. The study was not powered for efficacy, and none of the efficacy variables demonstrated statistical significance. Favorable trends were seen in the 2-mg/kg group as compared with placebo in median intensive care unit length of stay (5 vs. 9 days) and median time on ventilator (34 vs. 72 hours). Conclusions: A single 2-mg/kg dose of rhuMAb CD18 maintains greater than 90% saturation of neutrophil CD18 receptors for approximately 48 hours in patients with traumatic hemorrhagic shock undergoing resuscitation. There was no trend toward increased infection. A larger trial is needed to demonstrate the Clinical efficacy of rhuMAb CD18, perhaps using more reliable endpoints.

AB - Background: Activated neutrophils have been shown to play a pivotal role in resuscitation injury after traumatic hemorrhagic shock. Blocking the adhesion of neutrophils with a recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) may reduce resuscitation injury but increase the risk of infection. This was a dose-finding phase II study to determine safety, pharmacokinetics, pharmacodynamics, and clinical outcome parameters for additional studies. Methods: This was a prospective, placebo-controlled, randomized (3:1), double-blind phase II trial enrolling 116 blunt and penetrating trauma patients from 14 trauma centers over a 9-month period. Patients with hypotension (blood pressure ≤90 mm Hg) from hemorrhagic shock were given a single intravenous dose of rhuMAb CD18 or placebo. The three doses tested were0.5, 1, and 2 mg/kg. The drug was administered within 4 hours of the hypotensive episode and no later than 6 hours from time of injury. Exclusion criteria included head injury resulting in Glasgow Coma Scale score less than 8 or a history of cardiopulmonary resuscitation in the trauma center. An independent Drug Safety and Monitoring Review Board periodically reviewed unblinded data for safety issues and to give approval for dose escalation. Results: Minor and major infection rates in rhuMAb CD18 groups were comparable to placebo. There war no evidence of antibody formation against rhuMAb CD18. Linear PK was observed within the dose range studied. Duration of neutrophil binding was dose-dependent, with 2 mg/kg resulting in greater than 90% neutrophil CD18 receptor saturation for approximately 48 hours. The mortality was 6.7% (2 of 30) in the placebo group, 4.8% (1 of 21) in the 0.5-mg/kg group, 8.5% (4 of 47) in the 1-mg/kg group, and 0% (0 of 18) in the 2-mg/kg group. The study was not powered for efficacy, and none of the efficacy variables demonstrated statistical significance. Favorable trends were seen in the 2-mg/kg group as compared with placebo in median intensive care unit length of stay (5 vs. 9 days) and median time on ventilator (34 vs. 72 hours). Conclusions: A single 2-mg/kg dose of rhuMAb CD18 maintains greater than 90% saturation of neutrophil CD18 receptors for approximately 48 hours in patients with traumatic hemorrhagic shock undergoing resuscitation. There was no trend toward increased infection. A larger trial is needed to demonstrate the Clinical efficacy of rhuMAb CD18, perhaps using more reliable endpoints.

KW - Acute lung injury

KW - Adult respiratory distress syndrome

KW - Infection

KW - Multiple organ dysfunction syndrome

KW - Neutrophils

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Safety

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