PMID- 22340283
OWN - NLM
STAT- MEDLINE
DCOM- 20130611
LR  - 20211021
IS  - 1466-609X (Electronic)
IS  - 1364-8535 (Print)
IS  - 1364-8535 (Linking)
VI  - 16
IP  - 1
DP  - 2012 Feb 17
TI  - 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.
PG  - R31
LID - 10.1186/cc11203 [doi]
AB  - INTRODUCTION: Tumor necrosis factor-alpha (TNF-alpha), 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-alpha 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-alpha 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.
FAU - Morris, Peter E
AU  - Morris PE
AD  - Wake Forest University School of Medicine, Winston Salem, NC, USA. 
      pemorris@wfubmc.edu
FAU - Zeno, Brian
AU  - Zeno B
FAU - Bernard, Andrew C
AU  - Bernard AC
FAU - Huang, Xiangning
AU  - Huang X
FAU - Das, Shampa
AU  - Das S
FAU - Edeki, Timi
AU  - Edeki T
FAU - Simonson, Steven G
AU  - Simonson SG
FAU - Bernard, Gordon R
AU  - Bernard GR
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20120217
PL  - England
TA  - Crit Care
JT  - Critical care (London, England)
JID - 9801902
RN  - 0 (Immunoglobulin Fab Fragments)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Animals
MH  - Cohort Studies
MH  - Double-Blind Method
MH  - Female
MH  - Humans
MH  - Immunoglobulin Fab Fragments/*administration & dosage/adverse effects/therapeutic 
      use
MH  - Infusions, Intravenous
MH  - Male
MH  - Middle Aged
MH  - Sepsis/diagnosis/drug therapy
MH  - *Severity of Illness Index
MH  - Sheep
MH  - Shock, Septic/diagnosis/*drug therapy
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/*immunology
PMC - PMC3396277
EDAT- 2012/02/22 06:00
MHDA- 2013/06/12 06:00
PMCR- 2012/02/17
CRDT- 2012/02/21 06:00
PHST- 2011/10/24 00:00 [received]
PHST- 2011/12/19 00:00 [revised]
PHST- 2012/02/17 00:00 [accepted]
PHST- 2012/02/21 06:00 [entrez]
PHST- 2012/02/22 06:00 [pubmed]
PHST- 2013/06/12 06:00 [medline]
PHST- 2012/02/17 00:00 [pmc-release]
AID - cc11203 [pii]
AID - 10.1186/cc11203 [doi]
PST - epublish
SO  - Crit Care. 2012 Feb 17;16(1):R31. doi: 10.1186/cc11203.