Liposomal prostaglandin E₁ (TLC C-53) in acute respiratory distress syndrome

A controlled, randomized, double-blind, multicenter clinical trial

Abstract

Objective 

To evaluate the safety and efficacy of an intravenous liposomal dispersion of prostaglandin E₁ 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 and university-affiliated 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 E₁ or placebo. The study drug was infused intravenously for 60 mins every 6 hrs for 7 days starting with a dosage of 0.15 [micro sign]g/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 [micro sign]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/FIO2 ratio (defined as first PaO_2/FIO2 >300 mm Hg), day 28 mortality, ventilator dependence at day 8, changes in PaO_2/FIO2, 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/FIO2, 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 E₁ (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 E₁ group compared with the placebo group (median number of days to off mechanical ventilation, 16.9 in patients receiving liposomal prostaglandin E₁ 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 E₁ group and 50 of 170 (29%) in patients receiving placebo; p = .55). In contrast, treatment with liposomal prostaglandin E₁ was associated with a significantly shorter time to reach a PaO_2/FIO (₂) ratio of >300 mm Hg (median number of days to reaching a PaO_2/FIO2 ratio >300 mm Hg: 9.8 days in the liposomal prostaglandin E₁ 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 [micro sign]g/kg) of liposomal prostaglandin E₁ (median number of days to discontinuation of ventilation, 10.3 in the liposomal prostaglandin E₁ 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 E₁ (40%) or placebo-treated (37%) groups. Drug-related adverse events of all kinds were reported in 69% of the patients receiving liposomal prostaglandin E₁ 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 E₁ accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival. (Crit Care Med 1999; 27:1478-1485)