title: A multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial assessing safety and efficacy of active site inactivated recombinant factor VIIa in subjects with acute lung injury or acute respiratory distress syndrome.
abstract: OBJECTIVE
  To evaluate the safety and efficacy of active site inactivated recombinant factor VIIa (FFR-rFVIIa) in patients with acute respiratory distress syndrome.
  
  
  METHODS
  Phase II, randomized, double-blind, placebo-controlled, dose-escalation trial.
  
  
  METHODS
  Forty-six intensive care units (ICU) in ten countries.
  
  
  METHODS
  All adult (>or=18 years), mechanically ventilated patients with acute onset (within 48 hour) of acute lung injury/acute respiratory distress syndrome were included.
  
  
  METHODS
  Four sequential (in ascending order) treatment groups (cohorts) in single and multiple dosing strategies. Subjects were randomized in a 2:1 ratio to either FFR-rFVIIa or placebo within each cohort.
  
  
  RESULTS
  Data were collected daily for 7 days and on days 14 and 28 for efficacy variables including hematology and coagulation parameters, plasma d-dimer levels, plasma interleukin-6 levels, vital signs, ventilator parameters, lung injury score, and Sequential Organ Failure Assessment score. The study was discontinued prematurely by the Safety Committee based on statistical analysis of the mortality in cohort 3 (4 x 400 microg/kg), which suggested that, after adjusting for prognostic covariates, 28-day mortality was significantly higher in this cohort than in the placebo group and time to death was significantly shorter. A total of 214 patients (147 male) were included in the trial, mean age 59 years (range, 24-85 years). Overall, there were no significant differences in mortality rates in treated and placebo patients (36/144 deaths FFR-rFVIIa, 15/70 placebo). There was no treatment effect of FFR-rFVIIa on vital signs, blood chemistry parameters, hematology parameters, or amount of transfusion products required. There was a trend to increased bleeding with increasing FFR-rFVIIa dose.
  
  
  CONCLUSIONS
  In this randomized double-blind, placebo- controlled, dose-escalation trial, FFR-rFVIIa had no beneficial effects on morbidity or outcome overall. The cohort of patients receiving 4 x 400 g/kg of FFR-rFVIIa had increased mortality rates compared with placebo-treated patients, and there was a trend to increased risk of serious bleeding with increasing doses.
authors.affiliation: Department of Intensive Care, Hôpital Erasme, Université libre de Bruxelles, Belgium. jlvincen@ulb.ac.be
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vincent
authors.forename: Antonio
authors.initials: A
authors.lastname: Artigas
authors.forename: Lars C
authors.initials: LC
authors.lastname: Petersen
authors.forename: Christian
authors.initials: C
authors.lastname: Meyer
mesh_terms: D055371:Acute Lung Injury / Q000150:complications / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004311:Double-Blind Method; D015942:Factor VIIa / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012128:Respiratory Distress Syndrome / Q000150:complications / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa