Safety and efficacy of affinity-purified, anti-tumor necrosis factor-alpha, ovine fab for injection (CytoFab) in severe sepsis.
OBJECTIVE
Tumor necrosis factor (TNF) is a critical inflammatory mediator in sepsis. This trial was designed to evaluate the safety and effectiveness of polyclonal ovine anti-TNF fragment antigen binding (Fab) fragments (CytoFab) on plasma TNF-alpha, interleukin-6 (IL-6), and interleukin-8 (IL-8) concentrations and the number of shock-free and ventilator-free days in severely septic patients.


METHODS
Phase II, randomized, blinded, placebo-controlled trial conducted from September 1997 to July 1998.


METHODS
Nineteen intensive care units in the United States and Canada.


METHODS
Eighty-one septic patients with either shock or two organ dysfunctions.


METHODS
Patients were randomized to receive CytoFab, infused as a 250-units/kg loading dose, followed by nine doses of 50 units/kg every 12 hrs, or 5 mg/kg human albumin as placebo.


RESULTS
CytoFab promptly reduced plasma TNF-alpha (p = .001) and IL-6 concentrations (p = .002) compared with placebo. CytoFab also significantly decreased TNF-alpha in bronchoalveolar lavage (BAL) fluid (p < .001). The number of shock-free days did not differ between CytoFab and placebo (10.7 vs. 9.4, respectively) (p = .270). CytoFab increased mean ventilator-free days (15.0 vs. 9.8 for placebo; p = .040) and ICU-free days (12.6 vs. 7.6 for placebo; p = .030) at day 28. All-cause, 28-day mortality rates were 37% (14/38) for placebo recipients, compared with 26% (11/43) for CytoFab recipients (p = .274). No differences in incidences of adverse events, laboratory, or vital sign abnormalities were observed between groups. Although 41% of CytoFab-treated patients developed detectable plasma levels of human anti-sheep antibodies, none demonstrated clinical manifestations during the 28-day study.


CONCLUSIONS
CytoFab is well tolerated in patients with severe sepsis, effectively reducing serum and BAL TNF-alpha and serum IL-6 concentrations and increasing the number of ventilator-free and ICU-free days at day 28.
Rice
Todd W
TW
Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
Wheeler
Arthur P
AP
Morris
Peter E
PE
Paz
Harold L
HL
Russell
James A
JA
Edens
Tonya R
TR
Bernard
Gordon R
GR
D000818:Animals; D000906:Antibodies / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D007362:Intensive Care Units / Q000706:statistics & numerical data; D015850:Interleukin-6 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012121:Respiration, Artificial / Q000706:statistics & numerical data; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality; D012756:Sheep / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors*
D000906:Antibodies; C513813:CytoFab; D007140:Immunoglobulin Fab Fragments; D007155:Immunologic Factors; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha