TY - JOUR
T1 - Safety and efficacy of affinity-purified, anti-tumor necrosis factor-α, ovine fab for injection (CytoFab) in severe sepsis
AU - Rice, Todd W.
AU - Wheeler, Arthur P.
AU - Morris, Peter E.
AU - Paz, Harold L.
AU - Russell, James A.
AU - Edens, Tonya R.
AU - Bernard, Gordon R.
PY - 2006/9
Y1 - 2006/9
N2 - 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-α, interleukin-6 (IL-6), and interleukin-8 (IL-8) concentrations and the number of shock-free and ventilator-free days in severely septic patients. DESIGN: Phase II, randomized, blinded, placebo-controlled trial conducted from September 1997 to July 1998. SETTING: Nineteen intensive care units in the United States and Canada. PATIENTS: Eighty-one septic patients with either shock or two organ dysfunctions. INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: CytoFab promptly reduced plasma TNF-α (p = .001) and IL-6 concentrations (p = .002) compared with placebo. CytoFab also significantly decreased TNF-α 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-α and serum IL-6 concentrations and increasing the number of ventilator-free and ICU-free days at day 28.
AB - 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-α, interleukin-6 (IL-6), and interleukin-8 (IL-8) concentrations and the number of shock-free and ventilator-free days in severely septic patients. DESIGN: Phase II, randomized, blinded, placebo-controlled trial conducted from September 1997 to July 1998. SETTING: Nineteen intensive care units in the United States and Canada. PATIENTS: Eighty-one septic patients with either shock or two organ dysfunctions. INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: CytoFab promptly reduced plasma TNF-α (p = .001) and IL-6 concentrations (p = .002) compared with placebo. CytoFab also significantly decreased TNF-α 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-α and serum IL-6 concentrations and increasing the number of ventilator-free and ICU-free days at day 28.
KW - Cytokines
KW - Phase II clinical trial
KW - Polyclonal
KW - Randomized controlled trial
KW - Septic shock
KW - Tumor necrosis factor-α
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U2 - 10.1097/01.CCM.0000230385.82679.34
DO - 10.1097/01.CCM.0000230385.82679.34
M3 - Article
C2 - 16810105
AN - SCOPUS:33747502519
SN - 0090-3493
VL - 34
SP - 2271
EP - 2281
JO - Critical Care Medicine
JF - Critical Care Medicine
IS - 9
ER -
