A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis.
OBJECTIVE
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.


METHODS
Randomized, double-blind, placebo-controlled trial.


METHODS
A total of 93 intensive care units worldwide.


METHODS
A total of 274 patients with severe sepsis and shock or respiratory failure.


METHODS
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 2.4 mg/kg/day.


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.


CONCLUSIONS
TAK-242 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.
Rice
Todd W
TW
Division of Allergy, Vanderbilt University School of Medicine, Nashville, TN, USA. todd.rice@vanderbilt.edu
Wheeler
Arthur P
AP
Bernard
Gordon R
GR
Vincent
Jean-Louis
JL
Angus
Derek C
DC
Aikawa
Naoki
N
Demeyer
Ignace
I
Sainati
Stephen
S
Amlot
Nicholas
N
Cao
Charlie
C
Ii
Masayuki
M
Matsuda
Hideyasu
H
Mouri
Kouji
K
Cohen
Jon
J
D000328:Adult; D000368:Aged; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D017052:Hospital Mortality / Q000639:trends*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000517:prevention & control; D011336:Probability; D020551:Pulse Therapy, Drug; D012016:Reference Values; D018570:Risk Assessment; D018805:Sepsis / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome
D016207:Cytokines; D013449:Sulfonamides; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate