To evaluate whether TAK-242
, a small-molecule inhibitor of Toll-like receptor-4
–mediated signaling, suppresses cytokine levels and improves 28-day all-cause mortality
rates in patients with severe sepsis
Randomized, double-blind, placebo-controlled trial.
A total of 93 intensive care units worldwide.
A total of 274 patients with severe sepsis
and shock or respiratory failure.
Patients were randomly assigned to receive a 30-min loading dose followed by 96-hr infusions of placebo, TAK-242
1.2 mg/kg/day, or TAK-242
Measurements and Main Results:
The primary pharmacodynamic end point was change in serum interleukin-6
levels relative to baseline, with 28-day all-cause mortality
rate the primary clinical end point. The trial was terminated because of a lack of effect of TAK-242
in suppressing serum interleukin-6
levels. A total of 274 subjects were randomly assigned and treated. Clinical parameters at baseline were balanced across the three groups. TAK-242
did not suppress interleukin-6
as measured by 0- to 96.5-hr area under the interleukin-6
concentration curve at either dose. Specifically, the area under the effect curve increased by 9% and 26.9% in the TAK-242
1.2 and 2.4 mg/kg/day groups, respectively, which was not statistically different from placebo (p
= .63 and .15, respectively). The 28-day mortality
rate was 24% in the placebo, 22% in the low-dose, and 17% in the high-dose group (p
= .26 for placebo vs. high dose). A nonsignificant reduction in mortality
rate was observed in a subset of patients with both shock and respiratory failure (placebo [n = 51], 33%, vs. high dose [n = 52], 19%, p
= .10). Transient, dose-related increases in methemoglobin levels were observed with TAK-242
treatment in 30.1% of the patients.
failed to suppress cytokine levels in patients with sepsis and shock or respiratory failure. Treatment with TAK-242
resulted in mild increases in serum methemoglobin levels but was otherwise well tolerated. Although observed mortality
rates in patients with both shock and respiratory failure were lower with the 2.4 mg/kg/day dose, differences were not significant.