Liposomal prostaglandin E-1 (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 wi th acute respiratory distress syndrome (ARDS). Design: Randomized, prospective, multicenter, double-blind, placebo-control led, phase III clinical trial. Setting: Forty-seven community acid university-affiliate hospitals in the U nited 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 rece ive either liposomal prostaglandin E-1 or placebo. The study drug was infus ed 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 d ose (3.6 mu g/kg/hr) was attained or intolerance to further increases devel oped. Patients received standard aggressive medical/surgical care during th e 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 impr ovement 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)/Fl o(2), incidence of and time to development/resolution of organ failure othe r than ARDS. Results: A total of 348 patients could be evaluated for efficacy. The distr ibution of variables at baseline describing gender, lung injury scores, Acu te Physiology and Chronic Health Evaluation II scores, Pao(2)/Flo(2), pulmo nary compliance, and time from onset of ARDS or from institution of mechani cal 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) trea tment arms. There was no significant difference in the number of days to th e discontinuation of ventilation in the liposomal prostaglandin E-1 group c ompared with the placebo group (median number of days to off mechanical ven tilation, 16.9 in patients receiving liposomal prostaglandin E-1 and 19.6 i n 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 patie nts receiving placebo; p = .55). In contrast, treatment with liposomal pros taglandin E-1 was associated with a significantly shorter time to reach a P ao(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 grou p and 13.7 days in patients receiving the placebo; p = .02). Among the subg roups examined, time to off mechanical ventilation was significantly reduce d in patients who received at least 85% of a full dose (i.e., > 45.9 mu g/k g) 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 day s in patients receiving placebo; p = .05), The overall incidence of serious adverse events was not significantly different in the liposomal prostaglan din E-1 (40%) or placebo-treated (37%) groups. Drug-related adverse events of all kinds were reported in 69% of the patients receiving liposomal prost aglandin E-1 compared with 33% of the placebo group, with hypotension and h ypoxia (occurring in 52% and 24% of the liposomal prostaglandin E-1-treated patients, respectively, and 17% and 5% of the placebo-treated patients, re spectively) being noted most frequently. Conclusions: In the intent-to-treat population of patients with ARDS, treat ment with liposomal prostaglandin E-1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation an d did not improve day 28 survival.