Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study

Objective: This study investigated whether treatment with the
anti-tumor necrosis factor-a monoclonal antibody afelimomab
would improve survival in septic patients with serum interleukin
(IL)-6 concentrations of >1000 pg/mL.
Design: Multicenter, double-blind, randomized, placebo-controlled
study.
Setting: Eighty-four intensive care units in academic medical
centers in Europe and Israel.
Patients: 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 5 224) or placebo (n 5 222).
Patients with a negative IL-6 test (n 5 498) were not randomized
and were followed up for 28 days.
Interventions: 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.
Measurements and Main 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.