title: A Phase II study of polyclonal anti-TNF-α (AZD9773) in Japanese patients with severe sepsis and/or septic shock.
abstract: Because tumor necrosis factor-alpha (TNF-α) induces many of the pathophysiological signs and symptoms observed in sepsis, it is a potential therapeutic target for treatment. The primary objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple intravenous (i.v.) infusions of two doses of AZD9773 in Japanese patients with severe sepsis and/or septic shock. In this Phase II, double-blind, placebo-controlled, dose-escalation study (ClinicalTrials.gov Identifier: NCT01144624), Japanese patients were randomized to two successive treatment cohorts (cohort 1, loading/maintenance doses of 250/50 U/kg or placebo; cohort 2, loading/maintenance doses of 500/100 U/kg or placebo) for a 5-day treatment period, then a follow-up period to day 29. Twenty patients were enrolled (AZD9773 cohort 1, n = 7; AZD9773 cohort 2, n = 7; placebo, n = 6), and all completed the study. Most treatment-emergent adverse events (TEAEs) were mild or moderate and none led to discontinuation. The most common TEAEs in the AZD9773 cohorts were pleural effusion (64.3%) and peripheral edema (28.6%). Pharmacokinetic data demonstrated an approximately proportional increase in concentration with increasing dose. Treatment with AZD9773 led to a decrease in TNF-α concentrations, which was more discernible in the AZD9773 cohort 2; TNF-α concentrations generally decreased with time in patients receiving placebo. A similar pattern of response was observed with interleukin-6 (IL-6) and IL-8. AZD9773 was generally well tolerated with dose-proportional pharmacokinetics in Japanese patients with severe sepsis/septic shock.
authors.affiliation: Keio University School of Medicine, 2-5-10 Minato Chuo-ku, Tokyo, 104-0043, Japan, aikawa7@rc4.so-net.ne.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Aikawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujimi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yoshihara
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Daikai
authors.initials: D
authors.lastname: Sadamitsu
authors.forename: Michiru
authors.initials: M
authors.lastname: Momozawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D007378:Interleukins / Q000097:blood; D007564:Japan; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: C587873:AZD9773; D000893:Anti-Inflammatory Agents; D007140:Immunoglobulin Fab Fragments; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha