Recombinant humanized monoclonal antibody against CD18 (rhuMAb CD18) in traumatic hemorrhagic shock: results of a phase II clinical trial. Traumatic Shock Group.
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 < or =90 mm Hg) from hemorrhagic shock were given a single intravenous dose of rhuMAb CD18 or placebo. The three doses tested were 0.5, 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 was 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.
Rhee
P
P
Trauma Services, Washington Hospital Center, DC 20010, USA. prhee@usuhs.mil
Morris
J
J
Durham
R
R
Hauser
C
C
Cipolle
M
M
Wilson
R
R
Luchette
F
F
McSwain
N
N
Miller
R
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D018821:CD18 Antigens / Q000276:immunology*; D003257:Consumer Product Safety; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000401:mortality; D012774:Shock, Traumatic / Q000188:drug therapy* / Q000401:mortality; D018709:Statistics, Nonparametric; D016019:Survival Analysis
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D011994:Recombinant Proteins