Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome:: A controlled, randomized, double-blind, multicenter clinical trial

Objective: To evaluate tbe safety and efficacy of an intravenous liposomal dispersion of prostaglandin E-1 as TLC C-53 in the treatment of patients with acute respiratory distress syndrome (ARDS). Design: Randomized, prospective, multicenter, double-blind, placebo-controlled, phase III clinical trial. Setting: Forty-seven community acid university-affiliate hospitals in the United States. Patients: A total of 350 patients with ARDS were enrolled in this clinical trial. Intervention: Patients were prospectively randomized in a 1:1 ratio to receive either liposomal prostaglandin E-1 or placebo. The study drug was infused intravenously for 60 mins every 6 hrs for 7 days starting with a dosage of 0.15 mu g/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 mu g/kg/hr) was attained or intolerance to further increases developed. Patients received standard aggressive medical/surgical care during the infusion period. Outcome Measures: The primary outcome measure was the time it took to wean the patient from the ventilator. Secondary end points included time to improvement of the Pao(2)/Flo(2) ratio (defined as first Pao(2)/Flo(2) >300 mm Hg), day 28 mortality, ventilator dependence at day 8, changes in Pao(2)/Flo(2), incidence of and time to development/resolution of organ failure other than ARDS. Results: A total of 348 patients could be evaluated for efficacy. The distribution of variables at baseline describing gender, lung injury scores, Acute Physiology and Chronic Health Evaluation II scores, Pao(2)/Flo(2), pulmonary compliance, and time from onset of ARDS or from institution of mechanical ventilation to the first dose of study drug was similar among patients in the liposomal prostaglandin E-1 (n = 177) and the placebo (n = 171) treatment arms. There was no significant difference in the number of days to the discontinuation of ventilation in the liposomal prostaglandin E-1 group compared with the placebo group (median number of days to off mechanical ventilation, 16.9 in patients receiving liposomal prostaglandin E-1 and 19.6 in those administered placebo; p = .94). Similarly, mortality at day 28 was not significantly different in the two groups (day 28 mortality, 57 of 176 (32%) in the liposomal prostaglandin E-1 group and 50 of 170 (29%) in patients receiving placebo; p = .55). In contrast, treatment with liposomal prostaglandin E-1 was associated with a significantly shorter time to reach a Pao(2)/Flo(2) ratio of >300 mm Hg (median number of days to reaching a Pao(2)/Flo(2) ratio >300 mm Hg: 9.8 days in the liposomal prostaglandin E-1 group and 13.7 days in patients receiving the placebo; p = .02). Among the subgroups examined, time to off mechanical ventilation was significantly reduced in patients who received at least 85% of a full dose (i.e., > 45.9 mu g/kg) of liposomal prostaglandin E-1 (median number of days to discontinuation of ventilation, 10.3 in the liposomal prostaglandin E-1 group and 16.3 days in patients receiving placebo; p = .05), The overall incidence of serious adverse events was not significantly different in the liposomal prostaglandin E-1 (40%) or placebo-treated (37%) groups. Drug-related adverse events of all kinds were reported in 69% of the patients receiving liposomal prostaglandin E-1 compared with 33% of the placebo group, with hypotension and hypoxia (occurring in 52% and 24% of the liposomal prostaglandin E-1-treated patients, respectively, and 17% and 5% of the placebo-treated patients, respectively) being noted most frequently. Conclusions: In the intent-to-treat population of patients with ARDS, treatment with liposomal prostaglandin E-1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival.