Safety and efficacy of affinity-purified, anti-tumor necrosis factor-alpha, ovine fab for injection (CytoFab) in severe sepsis.

Abstract

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.

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-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.

• Authors: Todd W Rice, Arthur P Wheeler, Peter E Morris, Harold L Paz, James A Russell, Tonya R Edens, Gordon R Bernard
• Journal: Critical care medicine (Crit Care Med) Vol. 34 Issue 9 Pg. 2271-81 (Sep 2006) ISSN: 0090-3493 [Print] United States
• PMID: 16810105 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Comment)

Chemical References

• Antibodies
• CytoFab
• Immunoglobulin Fab Fragments
• Immunologic Factors
• Interleukin-6
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Antibodies (blood)
• Bronchoalveolar Lavage Fluid (chemistry)
• Double-Blind Method
• Female
• Humans
• Immunoglobulin Fab Fragments (therapeutic use)
• Immunologic Factors (therapeutic use)
• Infusions, Intravenous
• Intensive Care Units (statistics & numerical data)
• Interleukin-6 (analysis)
• Male
• Middle Aged
• Prospective Studies
• Respiration, Artificial (statistics & numerical data)
• Sepsis (drug therapy, mortality)
• Sheep (immunology)
• Tumor Necrosis Factor-alpha (analysis, antagonists & inhibitors)