Panacek EA, Marshall JC, Albertson TE, et al: Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab′)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels

Department of Surgery, University of Toronto, Toronto, Ontario, Canada
Critical Care Medicine (Impact Factor: 6.31). 12/2004; 32(11):2173-82. DOI: 10.1097/01.CCM.0000145229.59014.6c
Source: PubMed


To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6.
Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial.
One hundred fifty-seven intensive care units in the United States and Canada.
Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels.
Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result.
In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo.
Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.

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    • "The results are also encouraging because patients with higher IL-6 levels had significantly higher mortality rates in the placebo group than those with lower IL-6 levels. Thus, this showed that afelimomab had a greater effect in patients at higher risk of mortality [28]. In a similar investigation, cytofab, a preparation of polyclonal ovine anti-TNF Fab IgG fragments, was tested in a phase II placebo-controlled randomized clinical trial in 81 septic patients with shock or two organ dysfunctions. "
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    ABSTRACT: The clinical process of severe sepsis is characterized by extreme inflammation interlinked with potent stimulation of the coagulation cascade often followed by a state of relative immune paralysis. In this paper, we will review many of the potential therapies directed at various steps along the inflammatory cascade from modulation of inflammatory mediators eliciting the immune response, alteration of the host's immune response in both a stimulatory and depressive manner, and taming the overexuberant coagulation response triggered by the fierce coagulation-inflammation cycle. Finally, we will discuss further opportunities for research to improve our ability to design effective therapies.
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    • "Several immunomodulatory therapies have been evaluated in sepsis. Corticosteroids [11,12], anti Tumor Necrosis Factor α (TNF α) antibodies [13,14], Anti Interleukin 1 antibodies [15], Platelet Aggregating Factor (PAF) antagonist [16,17], antioxidants especially selenium [18,19], modulation of nutrition [20], modulation of coagulation [21] and complement pathway [22] are examples of immunotherapy in sepsis, but none of them were effective on survival of patients. Procedures such as plasmapheresis and hemofiltration slightly improve prognosis of sepsis by reducing circulating levels of inflammatory cytokines but couldn’t decrease mortality rate [23]. "
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    ABSTRACT: Septimeb is a new herbal-derived remedy, recently approved for its potential immunomodulatory effects. Regarding the key role of immune system in the pathogenesis of severe sepsis and lack of any standard treatment for improving survival of these patients; we evaluated the effect of Septimeb -as an adjutant to standard treatment-on inflammatory biomarkers and mortality rates in patients with severe sepsis. In this multicenter, randomized, single-blind trial, we assigned patients with severe sepsis and Acute Physiology and Chronic Health Evaluation (APACHE II) score of more than 20 to receive standard treatment of severe sepsis (control group) or standard treatment plus Septimeb. This group was treated with Septimeb for 14 days then followed up for another14 days. APACHE score, Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score (SAPS) were calculated daily. Blood samples were analyzed for interleukin 2 tumor necrosis factor-α, total antioxidant power, platelet growth factor and matrix metalloproteinase 2. A total of 29 patients underwent randomization (13 in control group and 16 in Septimeb group). There was significant difference between the Septimeb and control group in the 14 days mortality rate (18.8% vs. 53.85 respectively, P=0.048). Compared to control group, Septimeb was significantly effective in improving SAPS (P= 0.029), SOFA (P=0.003) and APACHE II (P=0.008) scores. Inflammatory biomarkers didn't change significantly between the two groups (P>0.05). Septimeb reduces mortality rates among patients with severe sepsis and it could be added as a safe adjutant to standard treatment of sepsis.
    Full-text · Article · Sep 2012 · DARU-JOURNAL OF FACULTY OF PHARMACY
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    • "Efforts to block one or more aspects of the sepsis-associated inflammatory pathways have had little impact on patient survival. Of many drugs tested, few have demonstrated efficacy [Panacek, EA. et al. (2004), Bernard, GR. et al. (2001), Abraham, E. (2005), Ely, EW. et al. (2002)]. Clinical reports are consistent with the involvement of ROS/RNS in neonatal sepsis and its complications. "

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