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

Edward A. Panacek, John C. Marshall, Timothy E. Albertson, David H. Johnson, Steven Johnson, Rodger David MacArthur, Mark Miller, William T. Barchuk, Steven Fischkoff, Martin Kaul, Leah Teoh, Lori Van Meter, Lothar Daum, Stanley Lemeshow, Gregory Hicklin, Christopher Doig

Research output: Contribution to journalArticle

250 Citations (Scopus)

Abstract

Objective: 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. Design: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. Setting: One hundred fifty-seven intensive care units in the United States and Canada. Patients: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. Interventions: 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. Measurements and Main Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)2173-2182
Number of pages10
JournalCritical care medicine
Volume32
Issue number11
DOIs
StatePublished - Nov 1 2004
Externally publishedYes

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Interleukin-6
Sepsis
Tumor Necrosis Factor-alpha
Safety
Antibodies
Placebos
Mortality
afelimomab
Organ Dysfunction Scores
Population
Immunoglobulin Fragments
Phase III Clinical Trials
Risk Reduction Behavior
Serum
Canada
Intensive Care Units
Logistic Models
Monoclonal Antibodies
Regression Analysis
Infection

Keywords

  • Clinical trial
  • Interleukin-6
  • Monoclonal antibody
  • Sepsis
  • Sepsis syndrome
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

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. / Panacek, Edward A.; Marshall, John C.; Albertson, Timothy E.; Johnson, David H.; Johnson, Steven; MacArthur, Rodger David; Miller, Mark; Barchuk, William T.; Fischkoff, Steven; Kaul, Martin; Teoh, Leah; Van Meter, Lori; Daum, Lothar; Lemeshow, Stanley; Hicklin, Gregory; Doig, Christopher.

In: Critical care medicine, Vol. 32, No. 11, 01.11.2004, p. 2173-2182.

Research output: Contribution to journalArticle

Panacek, EA, Marshall, JC, Albertson, TE, Johnson, DH, Johnson, S, MacArthur, RD, Miller, M, Barchuk, WT, Fischkoff, S, Kaul, M, Teoh, L, Van Meter, L, Daum, L, Lemeshow, S, Hicklin, G & Doig, C 2004, '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', Critical care medicine, vol. 32, no. 11, pp. 2173-2182. https://doi.org/10.1097/01.CCM.0000145229.59014.6C
Panacek, Edward A. ; Marshall, John C. ; Albertson, Timothy E. ; Johnson, David H. ; Johnson, Steven ; MacArthur, Rodger David ; Miller, Mark ; Barchuk, William T. ; Fischkoff, Steven ; Kaul, Martin ; Teoh, Leah ; Van Meter, Lori ; Daum, Lothar ; Lemeshow, Stanley ; Hicklin, Gregory ; Doig, Christopher. / 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. In: Critical care medicine. 2004 ; Vol. 32, No. 11. pp. 2173-2182.
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abstract = "Objective: 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. Design: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. Setting: One hundred fifty-seven intensive care units in the United States and Canada. Patients: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. Interventions: 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. Measurements and Main Results: 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. Conclusions: 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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TY - JOUR

T1 - 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

AU - Panacek, Edward A.

AU - Marshall, John C.

AU - Albertson, Timothy E.

AU - Johnson, David H.

AU - Johnson, Steven

AU - MacArthur, Rodger David

AU - Miller, Mark

AU - Barchuk, William T.

AU - Fischkoff, Steven

AU - Kaul, Martin

AU - Teoh, Leah

AU - Van Meter, Lori

AU - Daum, Lothar

AU - Lemeshow, Stanley

AU - Hicklin, Gregory

AU - Doig, Christopher

PY - 2004/11/1

Y1 - 2004/11/1

N2 - Objective: 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. Design: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. Setting: One hundred fifty-seven intensive care units in the United States and Canada. Patients: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. Interventions: 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. Measurements and Main Results: 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. Conclusions: 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.

AB - Objective: 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. Design: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. Setting: One hundred fifty-seven intensive care units in the United States and Canada. Patients: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. Interventions: 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. Measurements and Main Results: 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. Conclusions: 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.

KW - Clinical trial

KW - Interleukin-6

KW - Monoclonal antibody

KW - Sepsis

KW - Sepsis syndrome

KW - Tumor necrosis factor

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