Objective: To evaluate the safety and efficacy of active site inactivated recombinant factor VIIa (FFR-rFVIIa) in patients with acute respiratory distress syndrome. Design: Phase II, randomized, double-blind, placebo-controlled, dose-escalation trial. Setting: Forty-six intensive care units (ICU) in ten countries. Patients: All adult (≥18 years), mechanically ventilated patients with acute onset (within 48 hour) of acute lung injury/acute respiratory distress syndrome were included. Interventions: 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. Measurements and 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 × 400 μg/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. Conclusion: 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 × 400 μg/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. Copyright © 2009 by the Society of Critica lCare.