Intensive care medicine · 2001
A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-alpha antibody afelimomab in patients with sepsis syndrome.
Клиническое исследованиеКлиническое исследование I фазыКлиническое исследование II фазыСтатьяМногоцентровое исследованиеРандомизированное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Gallagher J, Fisher C, Sherman B, Munger M, Meyers B, Ellison T, Fischkoff S, Barchuk W T, Teoh L, Velagapudi R
Аннотация
OBJECTIVE: To investigate the pharmacokinetics and safety of afelimomab, a murine antibody fragment against human tumor necrosis factor (TNF)-alpha 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.
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.