title: A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock.
abstract: BACKGROUND
  Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters.
  
  
  METHODS
  In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo.
  
  
  RESULTS
  Seventy patients received AZD9773 (n=47) or placebo (n=23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment.
  
  
  CONCLUSIONS
  The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies.
authors.affiliation: Wake Forest University School of Medicine, Winston Salem, NC, USA. pemorris@wfubmc.edu
authors.forename: Peter E
authors.initials: PE
authors.lastname: Morris
authors.forename: Brian
authors.initials: B
authors.lastname: Zeno
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Bernard
authors.forename: Xiangning
authors.initials: X
authors.lastname: Huang
authors.forename: Shampa
authors.initials: S
authors.lastname: Das
authors.forename: Timi
authors.initials: T
authors.lastname: Edeki
authors.forename: Steven G
authors.initials: SG
authors.lastname: Simonson
authors.forename: Gordon R
authors.initials: GR
authors.lastname: Bernard
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D018805:Sepsis / Q000175:diagnosis / Q000188:drug therapy; D012720:Severity of Illness Index; D012756:Sheep; D012772:Shock, Septic / Q000175:diagnosis / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology*
chemical_list: D007140:Immunoglobulin Fab Fragments; D014409:Tumor Necrosis Factor-alpha