PMID- 11700399
OWN - NLM
STAT- MEDLINE
DCOM- 20011207
LR  - 20220408
IS  - 0090-3493 (Print)
IS  - 0090-3493 (Linking)
VI  - 29
IP  - 11
DP  - 2001 Nov
TI  - 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.
PG  - 2081-9
AB  - OBJECTIVE: To identify a safe and potentially effective recombinant tissue factor 
      pathway inhibitor (rTFPI) dose for further clinical evaluation in patients with 
      severe sepsis. DESIGN: Prospective, randomized, single-blind, placebo-controlled, 
      dose escalation, multicenter, multinational phase II clinical trial. SETTING: 
      Thirty-eight intensive care units in the United States and Europe. PATIENTS: Two 
      hundred and ten subjects with severe sepsis who received standard supportive care 
      and antimicrobial therapy. INTERVENTIONS: Subjects received a continuous 
      intravenous infusion of placebo or rTFPI at 0.025 or 0.05 mg/kg/hr for 4 days (96 
      hrs). MEASUREMENTS AND MAIN 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.
FAU - Abraham, E
AU  - Abraham E
AD  - Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado 
      Health Sciences Center, Denver, CO 80262, USA. Edward.Abraham@USHSC.edu
FAU - Reinhart, K
AU  - Reinhart K
FAU - Svoboda, P
AU  - Svoboda P
FAU - Seibert, A
AU  - Seibert A
FAU - Olthoff, D
AU  - Olthoff D
FAU - Dal Nogare, A
AU  - Dal Nogare A
FAU - Postier, R
AU  - Postier R
FAU - Hempelmann, G
AU  - Hempelmann G
FAU - Butler, T
AU  - Butler T
FAU - Martin, E
AU  - Martin E
FAU - Zwingelstein, C
AU  - Zwingelstein C
FAU - Percell, S
AU  - Percell S
FAU - Shu, V
AU  - Shu V
FAU - Leighton, A
AU  - Leighton A
FAU - Creasey, A A
AU  - Creasey AA
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Crit Care Med
JT  - Critical care medicine
JID - 0355501
RN  - 0 (Lipoproteins)
RN  - 0 (lipoprotein-associated coagulation inhibitor)
SB  - IM
MH  - APACHE
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Infusions, Intravenous
MH  - Intensive Care Units
MH  - International Normalized Ratio
MH  - Lipoproteins/administration & dosage/blood/*therapeutic use
MH  - Male
MH  - Middle Aged
MH  - Sepsis/classification/*drug therapy/mortality
MH  - Survival Rate
EDAT- 2001/11/09 10:00
MHDA- 2002/01/05 10:01
CRDT- 2001/11/09 10:00
PHST- 2001/11/09 10:00 [pubmed]
PHST- 2002/01/05 10:01 [medline]
PHST- 2001/11/09 10:00 [entrez]
AID - 10.1097/00003246-200111000-00007 [doi]
PST - ppublish
SO  - Crit Care Med. 2001 Nov;29(11):2081-9. doi: 10.1097/00003246-200111000-00007.