title: Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study.
abstract: OBJECTIVE
  This study investigated whether treatment with the anti-tumor necrosis factor-alpha monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/mL.
  
  
  METHODS
  Multicenter, double-blind, randomized, placebo-controlled study.
  
  
  METHODS
  Eighty-four intensive care units in academic medical centers in Europe and Israel.
  
  
  METHODS
  A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222). Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days.
  
  
  METHODS
  Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered.
  
  
  RESULTS
  The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p <.001) than that found in the randomized patients (55.8%, 249 of 446). The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs. 57.7% (128 of 222), respectively. Treatment with afelimomab was not associated with any particular adverse events.
  
  
  CONCLUSIONS
  The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.
authors.affiliation: Department of Anesthesia and Operative Intensive Care, Friedrich-Schiller University, Jena, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Reinhart
authors.forename: T
authors.initials: T
authors.lastname: Menges
authors.forename: B
authors.initials: B
authors.lastname: Gardlund
authors.forename: J
authors.initials: J
authors.lastname: Harm Zwaveling
authors.forename: M
authors.initials: M
authors.lastname: Smithes
authors.forename: J L
authors.initials: JL
authors.lastname: Vincent
authors.forename: J M
authors.initials: JM
authors.lastname: Tellado
authors.forename: A
authors.initials: A
authors.lastname: Salgado-Remigio
authors.forename: R
authors.initials: R
authors.lastname: Zimlichman
authors.forename: S
authors.initials: S
authors.lastname: Withington
authors.forename: K
authors.initials: K
authors.lastname: Tschaikowsky
authors.forename: R
authors.initials: R
authors.lastname: Brase
authors.forename: P
authors.initials: P
authors.lastname: Damas
authors.forename: H
authors.initials: H
authors.lastname: Kupper
authors.forename: J
authors.initials: J
authors.lastname: Kempeni
authors.forename: J
authors.initials: J
authors.lastname: Eiselstein
authors.forename: M
authors.initials: M
authors.lastname: Kaul
mesh_terms: D018806:APACHE; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D012044:Regression Analysis; D018805:Sepsis / Q000097:blood / Q000145:classification / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; C427683:afelimomab