A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-α antibody afelimomab in patients with sepsis syndrome
Autor: | Charles J. Fisher, Raja B. Velagapudi, Travis Ellison, Bruce Meyers, Mark A. Munger, Leah Teoh, William T. Barchuk, Steven Fischkoff, James Gallagher, Bruce Sherman |
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Rok vydání: | 2001 |
Předmět: |
Adult
Male medicine.medical_specialty Critical Care and Intensive Care Medicine Placebo Gastroenterology law.invention Sepsis Randomized controlled trial law Intensive care Internal medicine Humans Medicine Adverse effect Aged Analysis of Variance Dose-Response Relationship Drug Interleukin-6 Tumor Necrosis Factor-alpha business.industry Septic shock Antibodies Monoclonal Middle Aged medicine.disease Systemic Inflammatory Response Syndrome United States Surgery Survival Rate Clinical trial Logistic Models Consumer Product Safety Afelimomab Female business Half-Life medicine.drug |
Zdroj: | Intensive Care Medicine. 27:1169-1178 |
ISSN: | 1432-1238 0342-4642 |
Popis: | Objective: To investigate the pharmacokinetics and safety of afelimomab, a murine antibody fragment against human tumor necrosis factor (TNF)-α in patients with sepsis. Design: Multicenter, randomized, open-label, placebo-controlled phase I/II clinical trial. Setting: Intensive care units of six academic medical centers in the United States. Patients: Forty-eight patients with a clinical diagnosis of sepsis who received standard supportive care and antimicrobial therapy. Interventions: Patients received 0.3, 1.0, or 3.0 mg/kg afelimomab or placebo intravenously over 20 min. Three patients in each dose group received single doses; the remaining nine patients in each group received multiple (nine) doses at 8-h intervals over 72 h. Measurements and main results: Afelimomab appeared safe and well tolerated. Single- and multiple-dose kinetics were predictable and dose related. The elimination half-life was 44.7 h. Afelimomab treatment resulted in increased serum concentrations of TNF (includes TNF-antibody complexes) and decreased serum interleukin-6 concentrations, whereas no discernible trends were observed in placebo-treated patients. There was no significant treatment effect on 28-day mortality as was expected given the small number of patients. However, overall mortality was significantly (p=0.001) associated with baseline interleukin-6 concentration. All patients experienced adverse events, but the vast majority were considered unrelated to the study drug and demonstrated no apparent relationship to afelimomab dose. Although 41% of patients developed human anti-murine antibodies, there were no clinical sequelae. Conclusions: Multidose therapy with afelimomab was safe, well tolerated, and had predictable linear kinetics. A large randomized trial comparing afelimomab to placebo in patients with well defined sepsis has recently been completed. |
Databáze: | OpenAIRE |
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