A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-alpha antibody afelimomab in patients with sepsis syndrome.

Abstract

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.

• Authors: J Gallagher, C Fisher, B Sherman, M Munger, B Meyers, T Ellison, S Fischkoff, W T Barchuk, L Teoh, R Velagapudi
• Journal: Intensive care medicine (Intensive Care Med) Vol. 27 Issue 7 Pg. 1169-78 (Jul 2001) ISSN: 0342-4642 [Print] United States
• PMID: 11534565 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Interleukin-6
• Tumor Necrosis Factor-alpha
• afelimomab

Topics

• Adult
• Aged
• Analysis of Variance
• Antibodies, Monoclonal (administration & dosage, pharmacokinetics)
• Consumer Product Safety
• Dose-Response Relationship, Drug
• Female
• Half-Life
• Humans
• Interleukin-6 (blood)
• Logistic Models
• Male
• Middle Aged
• Survival Rate
• Systemic Inflammatory Response Syndrome (drug therapy, mortality)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)
• United States (epidemiology)