A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis*
| Autor: | Nicholas Amlot, Jonathan Cohen, Jean Louis Vincent, Naoki Aikawa, Kouji Mouri, Masayuki Ii, Arthur P. Wheeler, Ignace Demeyer, Stephen Sainati, Gordon R. Bernard, Derek C. Angus, Charlie Cao, Hideyasu Matsuda, Todd W. Rice |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male medicine.medical_specialty Multiple Organ Failure Placebo-controlled study Critical Care and Intensive Care Medicine Placebo Risk Assessment Loading dose Drug Administration Schedule Sepsis Double-Blind Method Reference Values Intensive care medicine Humans Hospital Mortality Infusions Intravenous Aged Probability Sulfonamides Dose-Response Relationship Drug business.industry Mortality rate Middle Aged medicine.disease Survival Analysis Surgery Treatment Outcome Respiratory failure Pulse Therapy Drug Shock (circulatory) Anesthesia Cytokines Female medicine.symptom business Follow-Up Studies |
| Zdroj: | Critical Care Medicine. 38:1685-1694 |
| ISSN: | 0090-3493 |
| Popis: | 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. Design: Randomized, double-blind, placebo-controlled trial. Setting: A total of 93 intensive care units worldwide. Patients: A total of 274 patients with severe sepsis and shock or respiratory failure. Interventions: 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. 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. 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. |
| Databáze: | OpenAIRE |
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