title: Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.
abstract: OBJECTIVE
  To identify a safe and potentially effective recombinant tissue factor pathway inhibitor (rTFPI) dose for further clinical evaluation in patients with severe sepsis.
  
  
  METHODS
  Prospective, randomized, single-blind, placebo-controlled, dose escalation, multicenter, multinational phase II clinical trial.
  
  
  METHODS
  Thirty-eight intensive care units in the United States and Europe.
  
  
  METHODS
  Two hundred and ten subjects with severe sepsis who received standard supportive care and antimicrobial therapy.
  
  
  METHODS
  Subjects received a continuous intravenous infusion of placebo or rTFPI at 0.025 or 0.05 mg/kg/hr for 4 days (96 hrs).
  
  
  RESULTS
  There were no significant imbalances in demographics, severity of illness, or source of infection in patients randomized to placebo or either dose of rTFPI. A 20% relative reduction in 28-day all-cause mortality was observed when all rTFPI-treated patients were compared with all placebo patients. An improvement in pulmonary organ dysfunction score and in a composite intensive care unit score (pulmonary, cardiovascular, and coagulation) were also noted in the rTFPI-treated patients. Logistic regression modeling indicated a substantial treatment by baseline laboratory international normalized ratio (INR) interaction effect when only treatment and INR were in the model (p =.037) and when baseline Acute Physiology and Chronic Health Evaluation (APACHE II) and log10 interleukin 6 were adjusted for (p =.026). This interaction effect indicates that higher baseline INR is associated with a more pronounced beneficial rTFPI effect. There was no increase in mortality in subjects treated with either dose of rTFPI compared with placebo. Biological activity, as detected by a statistically significant reduction in thrombin-antithrombin complexes (TATc), was noted in the all rTFPI-treated patients compared with those receiving placebo. There were no major imbalances across all treatment groups with respect to safety. The frequency of adverse events (AEs) and severe adverse events (SAEs) was similar among the treatment groups, with a slight increase in SAEs and SAEs involving bleeding in the 0.05 mg/kg/hr rTFPI group. The overall incidence of AEs involving bleeding was 28% of patients in the all placebo group and 23% of patients in the all rTFPI-treated group; a slight but statistically insignificant increase in incidence of SAEs involving bleeding was observed in the all rTFPI group (9%) as compared with the all placebo group (6%; p =.39).
  
  
  CONCLUSIONS
  Although the trial was not powered to show efficacy, a trend toward reduction in 28-day all-cause mortality was observed in the all rTFPI group compared with all placebo. This study demonstrates that rTFPI doses of 0.025 and 0.05 mg/kg/hr could be safely administered to severe sepsis patients. Additionally, rTFPI demonstrated bioactivity, as shown by reduction in TATc complexes and interleukin-6 levels. These findings warrant further evaluation of rTFPI in an adequately powered, placebo controlled, randomized trial for the treatment of severe sepsis.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA. Edward.Abraham@USHSC.edu
authors.forename: E
authors.initials: E
authors.lastname: Abraham
authors.forename: K
authors.initials: K
authors.lastname: Reinhart
authors.forename: P
authors.initials: P
authors.lastname: Svoboda
authors.forename: A
authors.initials: A
authors.lastname: Seibert
authors.forename: D
authors.initials: D
authors.lastname: Olthoff
authors.forename: A
authors.initials: A
authors.lastname: Dal Nogare
authors.forename: R
authors.initials: R
authors.lastname: Postier
authors.forename: G
authors.initials: G
authors.lastname: Hempelmann
authors.forename: T
authors.initials: T
authors.lastname: Butler
authors.forename: E
authors.initials: E
authors.lastname: Martin
authors.forename: C
authors.initials: C
authors.lastname: Zwingelstein
authors.forename: S
authors.initials: S
authors.lastname: Percell
authors.forename: V
authors.initials: V
authors.lastname: Shu
authors.forename: A
authors.initials: A
authors.lastname: Leighton
authors.forename: A A
authors.initials: AA
authors.lastname: Creasey
mesh_terms: D018806:APACHE; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007362:Intensive Care Units; D019934:International Normalized Ratio; D008074:Lipoproteins / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018805:Sepsis / Q000145:classification / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate
chemical_list: D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor