Cited by 516Sepsis Diagnosis and TreatmentImmune Response and InflammationInflammation biomarkers and pathways

The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.

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

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Rice, Todd W., Wheeler, Arthur P., Bernard, Gordon R., Vincent, Jean-Louis, Angus, Derek C., Aikawa, Naoki, Demeyer, Ignace, Sainati, Stephen, Amlot, Nicholas, Cao, Charlie, Ii, Masayuki, Matsuda, Hideyasu, Mouri, Kouji, Cohen, Jon·2010·Critical Care Medicine

DOI 10.1097/ccm.0b013e3181e7c5c9

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Abstract

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.

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Authors: Rice, T. W., Wheeler, A. P., Bernard, G. R., Vincent, J.-L., Angus, D. C., Aikawa, N., Demeyer, I., Sainati, S., Amlot, N., Cao, C., Ii, M., Matsuda, H., Mouri, K., & Cohen, J.
Affiliations: Vanderbilt University (US)
ORCID: Rice, Todd W.
Bernard, Gordon R.
Vincent, Jean-Louis
Angus, Derek C.
Demeyer, Ignace
Venue: Critical Care Medicine
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2010-08
Volume: 38
Issue: 8
Pages: 1685-1694
ISSN: 0090-3493 (ISSN-L)
DOI: 10.1097/ccm.0b013e3181e7c5c9
OpenAlex: W2053189438
Cited by: 512
References: 59
Citations by year: 2026: 34 · 2025: 37 · 2024: 35 · 2023: 35 · 2022: 38 · 2021: 45 · 2020: 49 · 2019: 38 · 2018: 36 · 2017: 30 · 2016: 25 · 2015: 16 · 2014: 23 · 2013: 25 · 2012: 27
FWCI: 16.99
Type: journal article
Language: en
Open access: green
figshare.com
Licence: cc-by
Locations: Critical Care Medicine (publishedVersion)
PubMed (publishedVersion)
Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
Figshare (submittedVersion, cc-by)
Topics: Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords: sepsis, interleukin-6, cytokine inhibition, septic shock, respiratory failure, 28-day mortality, methemoglobinemia, drug safety, intensive care unit patients, dose comparison, pharmacodynamics
MeSH terms: Adult, Aged, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Infusions, Intravenous, Male, Middle Aged, Multiple Organ Failure, Probability, Reference Values, Sulfonamides, Survival Analysis, Cytokines, Treatment Outcome, Hospital Mortality, Risk Assessment, Sepsis, Pulse Therapy, Drug

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

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