A multicenter, randomized, controlled trial of lucinactant versus poractant alfa among very premature infants at high risk for respiratory distress syndrome.

摘要

BACKGROUND: Available therapeutic surfactants are either animal-derived or non-protein-containing synthetic products. Animal-derived surfactants contain variable amounts of surfactant apoproteins, whereas the older-generation synthetic products contain only phospholipids and lack surfactant proteins (SPs). Both decrease morbidity and mortality rates associated with respiratory distress syndrome (RDS) among preterm infants, compared with placebo. However, excess mortality rates have been observed with non-protein-containing synthetic surfactants, compared with the animal-derived products. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved with the addition of peptides that are functional analogs of SPs. Lucinactant is a new synthetic peptide-containing surfactant that contains sinapultide, a novel, 21-amino acid peptide (leucine and lysine repeating units, KL4 peptide) designed to mimic human SP-B. It is completely devoid of animal-derived components. OBJECTIVE: We hypothesized that the outcomes for premature infants treated with lucinactant and poractant alfa would be similar. Therefore, we compared lucinactant (Surfaxin; Discovery Laboratories, Doylestown, PA) with porcine-derived, poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) in a trial to test for noninferiority. METHODS: A total of 252 infants born between 24 and 28 weeks of completed gestation, with birth weights between 600 and 1250 g, were assigned randomly in a multicenter, multinational, noninferiority, randomized, controlled study to receive either lucinactant (n = 124) or poractant alfa (n = 128) within 30 minutes of life. The primary outcome was the incidence of being alive without bronchopulmonary dysplasia (BPD) through 28 days of age. Key secondary outcomes included death at day 28 and 36 weeks postmenstrual age (PMA), air leaks, neuroimaging abnormalities, and other complications related to either prematurity or RDS. An independent, international, data and safety monitoring committee monitored the trial. RESULTS: The treatment difference between lucinactant and poractant alfa for survival without BPD through 28 days was 4.75% (95% confidence interval [CI]: -7.3% to 16.8%) in favor of lucinactant, with the lower boundary of the 95% CI for the difference, ie, -7.3%, being greater than the prespecified noninferiority margin of -14.5%. At 28 days, 45 of 119 infants given lucinactant were alive without BPD (37.8%; 95% CI: 29.1-46.5%), compared with 41 of 124 given poractant alfa (33.1%; 95% CI: 24.8-41.3%); at 36 weeks PMA, the rates were 64.7% and 66.9%, respectively. The corresponding mortality rate through day 28 for the lucinactant group was lower than that for the poractant alfa group (11.8% [95% CI: 6.0-17.6%] vs 16.1% [95% CI: 9.7-22.6%]), as was the rate at 36 weeks PMA (16% and 18.5%, respectively). There were no differences in major dosing complications. In addition, no significant differences were observed in the incidences of common complications of prematurity, includingintraventricular hemorrhage (grades 3 and 4) and cystic periventricular leukomalacia (lucinactant: 14.3%; poractant alfa: 16.9%). CONCLUSIONS: Lucinactant and poractant alfa were similar in terms of efficacy and safety when used for the prevention and treatment of RDS among preterm infants. The ability to enhance the performance of a synthetic surfactant with the addition of a peptide that mimics the action of SP-B, such as sinapultide, brings potential advantages to exogenous surfactant therapy.