Journal of Perinatology (2009) 29, S23–S28 r 2009 Nature Publishing Group All rights reserved. 0743-8346/09 $32 www.nature.com/jp REVIEW Synthetic surfactants: where are we? Evidence from randomized, controlled clinical trials

F Moya1,2 1Department of Neonatology, New Hanover Regional Medical Center, Wilmington, NC, USA and 2Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA

were shown in that meta-analysis or in any individual trials The benefits of exogenous synthetic or animal-derived surfactants for comparing these surfactants. None of these surfactant comparison prevention or treatment of respiratory distress syndrome (RDS) are well trials reported outcomes beyond the initial stay in the neonatal established. Data from head-to-head trials comparing animal-derived intensive care unit (NICU). surfactants primarily with the synthetic surfactant colfosceril suggest that Multiple studies have shown that synthetic surfactants lacking the major clinical advantages afforded by the presence of surfactant protein SP-B and SP-C fail to lower surface tension in vitro, whereas (SP)-B and SP-C in animal-derived preparations relate to faster onset of animal-derived surfactants can reduce it to an extent somewhat action, a reduction in the incidence of RDS when used prophylactically, and directly related to their SP content.3,4 The absence of SP-B seems to a lower incidence of air leaks and RDS-related deaths. However, no benefits be particularly important as animals or humans lacking SP-B in terms of overall mortality or BPD have been shown in these head-to-head because of a genetic mutation develop a fatal form of respiratory comparisons. Findings from trials of a new-generation synthetic surfactant failure during the neonatal period.5,6 In contrast, individuals with containing a peptide that mimics SP-B, as well as their follow-up study mutations in SP-C develop interstitial lung disease as adults rather suggest that its administration improves short-term clinical outcomes than respiratory disease during the neonatal period.7 compared with colfosceril and results in survival through 1 year of age, The purpose of this review is to summarize the results from which is at least comparable, if not perhaps superior, to that seen with published randomized trials comparing animal-derived with animal-derived surfactants. synthetic surfactants devoid of proteins and to review the evidence Journal of Perinatology (2009) 29, S23–S28; doi:10.1038/jp.2009.26 from clinical trials of a new-generation synthetic surfactant that 8 Keywords: surfactant; respiratory distress syndrome; bronchopulmonary contains phospholipids and a peptide that mimics SP-B. For a dysplasia; infant/newborn summary of all published head-to-head comparison trials of surfactants, including comparisons between animal-derived surfactants, the reader is referred to the recent review by Moya and Maturana.9 Introduction Animal-derived surfactants from bovine or porcine sources currently in clinical use contain various phospholipids and variable quantities of surfactant proteins (SP)-B and -C, whereas currently Composition of commonly used surfactants available synthetic surfactants contain only phospholipids and no The main characteristics and components of the most studied and surfactant proteins.1 Although synthetic surfactants have potential used synthetic and animal-derived surfactants are found in safety advantages over animal-derived products, they seem to be Table 1. The amount of phospholipids administered per dose of clinically inferior to animal-derived surfactants. This assertion is surfactant is quite variable and ranges from 50 to 200 mg kg–1. based primarily on the results of a meta-analysis of 11 controlled The volume of each dose and interval for administration trials comparing these two classes of surfactants, which showed a recommended by the various manufacturers are also different. marginally significant lower mortality and a lower risk of Colfosceril and pumactant contain no SPs. Animal-derived pneumothorax plus more rapid weaning with animal-derived surfactants differ in their contents of SP-B and SP-C.3 Calfactant surfactants compared with synthetic surfactants.2 However, no (Infasurf, Forest Laboratories, Inc., St Louis, MO, USA) contains the reductions in the incidence of bronchopulmonary dysplasia (BPD) highest concentration of SP-B on a weight basis, followed by poractant (Curosurf, Chiesi Farmaceutici, Parma, Italy). Beractant Correspondence: Dr F Moya, Department of Neonatology, New Hanover Regional Medical Center, 2131 South 17th Street, Wilmington, NC 28402-9025, USA. (Survanta, Ross Products Division, Abbott Laboratories, Columbus, E-mail: [email protected] OH, USA) has the lowest content of SP-B of these animal-derived Synthetic surfactants F Moya S24

Table 1 Main characteristics of surfactants commonly used or studied in neonates

Surfactant Family Main Proteins Phospholipid Suggested dose Phospholipid phospholipids concentration (mg mlÀ1) (ml kgÀ1) per dose (mg kgÀ1)

Colfosceril Synthetic DPPC No 13.5 5 67.5 Pumactant Synthetic DPPC, PG No 40 1.2 100 Beractant Animal-derived (bovine) DPPC, PG SP-B/SP-C 25 4 100 Calfactant Animal-derived (bovine) DPPC, PG SP-B/SP-C 35 3 105 Poractant Animal-derived (porcine) DPPC, PG SP-B/SP-C 80 1.25/2.5 100/200 Lucinactant Peptide-containing DPPC, POPG KL4 as SP-B 30 5.8 175 synthetic

Abbreviations: DPPC, dipalmitoylphosphatidylcholine; PG, phosphatidylglycerol; POPG, palmitoyloleylphosphatidylglycerol; SP-B, surfactant protein B; SP-C, surfactant protein C. surfactants. The content of the SP-B mimic in lucinactant recent lucinactant prophylaxis trial comparing this surfactant with (Surfaxin, Discovery Laboratories, Warrington, PA, USA) is colfosceril, in which infants were also randomized to beractant in a discussed later. 2:2:1 scheme.10–15 A major advantage of these studies lies in the fact that several thousand infants have been included. A major limitation in the design of these studies is that none of them were Controlled trials comparing non-protein-containing masked, except for the comparison included within the lucinactant synthetic with animal-derived surfactants trial. Moreover, the use of antenatal steroids in all but the Since the advent of exogenous surfactant therapy, several lucinactant trials was <40%, reflecting the time when they were animal-derived but only two synthetic surfactants devoid of SPs have conducted. The cumulative results show that overall mortality was been used clinically, namely colfosceril (Exosurf, GlaxoSmithKline, 18.4% for beractant and 20.9% for colfosceril (relative risk (RR) Brentford, UK) and pumactant (artificial lung expanding 0.89, 95% CI 0.75 to 1.05). Only the incidence of pneumothorax compound, Britannia Pharmaceuticals Ltd, Redhill, Surrey, was reduced using beractant versus colfosceril when used for England). Over the past decade and a half, there have been many treatment of RDS (RR 0.61, 95% CI 0.47 to 0.78) with a number randomized trials comparing these two major classes of surfactants, needed to treat (NNT) of 21, but not for prophylaxis of RDS. No although most have used a treatment rather than a prophylactic changes in need for supplemental oxygen at 36 weeks were noted approach. Soll and Blanco2 conducted a widely quoted systematic (23.5 versus 25.6%, respectively). Nonetheless, those trials for review of 11 trials comparing animal-derived surfactants with treatment of RDS in which ventilatory settings were reported synthetic surfactants. Seven of ten of the trials included in that showed more rapid reductions of supplemental oxygen and review compared colfosceril with beractant, two trials compared it ventilatory pressures among infants given beractant, which with calfactant and one trial with poractant alfa. Only one trial averaged about 7% lower FiO2 and 0.7 cm H2O lower mean airway compared the only other synthetic surfactant used clinically, pressure over the first 48 h. It should be noted that, when pumactant, with poractant. These authors concluded that both types colfosceril was compared with beractant using a prophylactic of surfactants are effective in the treatment and prevention of approach, a secondary comparison in one of the lucinactant trials, respiratory distress syndrome (RDS). However, they also concluded beractant reduced the incidence of RDS at 24 h (33.3 versus 47.2%, that, when taken together, use of animal-derived surfactants respectively), but did not result in less overall deaths, deaths due to 15 resulted in fewer deaths, greater early improvement in the RDS or other complications. requirement for ventilatory support and a lower overall incidence of Collectively, these data show that beractant has clinical pneumothorax than synthetic products containing only advantages such as less pneumothorax and more rapid weaning phospholipids. No advantages in terms of reduction in the incidence over colfosceril mainly when used for treatment of RDS, although of BPD were described in this systematic review or in any of the it is also more effective in prevention of RDS than colfosceril. individual trials included in it. In addition, a small but significant No benefits in terms of overall mortality or BPD have been shown. increase in the incidence of intraventricular hemorrhage (IVH) among infants treated with animal-derived surfactants was reported. Colfosceril versus calfactant There have been only two trials comparing colfosceril and Colfosceril versus beractant calfactant, one for prophylaxis and one for treatment of RDS.16,17 Five of the six published studies comparing colfosceril with These were large, multicenter trials that recruited almost two beractant were for treatment of RDS with the exception of the thousand infants, and had a more sophisticated design than the

Journal of Perinatology Synthetic surfactants F Moya S25 comparisons of beractant and poractant versus colfosceril, of RDS. The trial was conducted in three NICUs and the dose of including blinding and partial adjudication of primary outcomes. poractant used was 100 mg kg–1. The primary outcomes were the Antenatal steroids exposure was either not reported or occurred in duration of mechanical ventilation and supplemental oxygen. It less than one-third of the infants. Crossover use of surfactants was enrolled 230 infants, making it the third largest comparison trial of permitted, but there were no ventilatory guidelines. In the trial for poractant. Antenatal steroid use was better than in earlier trials at prophylaxis of RDS use of calfactant resulted in a lower incidence about 60%, but the study was not masked and there was also of RDS at 24 h (16 versus 42%, respectively, P<0.001) and in crossover use of surfactants. Consistent with other trials comparing RDS-related deaths (1.7 versus 5.4%, respectively, P ¼ 0.001). Also, animal-derived and synthetic surfactants without proteins, the infants given calfactant required less supplemental oxygen and group treated with poractant had lower oxygen requirements and mean airway pressure during the first 72 h after delivery. However, mean airway pressure during the first few hours after treatment. there were no significant differences in overall mortality analyzed However, there were no significant differences in overall mortality per protocol (15.1% in the calfactant group versus 17.5% in the (20.4% in the poractant group versus 13% in the colfosceril group; colfosceril group), use of oxygen at 36 weeks (11.8 versus 9.7%, RR 1.56, 95% CI 0.86 to 2.83), pneumothorax (9.7 and 9.6%, respectively) or pneumothorax (3.8 versus 6.1%, respectively), respectively) or oxygen use at 36 weeks (33.6 versus 27%, although the air leaks at 7 days were less frequent among infants respectively). Unexpectedly, the incidence of sepsis was significantly given calfactant. A concerning finding of this trial was the higher higher in the group treated with poractant (11 versus 4%, RR 3.17, incidence of severe IVH and PVL in the calfactant group (17.6 95% CI 1.05 to 9.52), a finding that has not been replicated in versus 11.4%, respectively; RR 1.54, 95% CI 1.11 to 2.14), although other studies. this may have been influenced by the lesser number of deaths due Similar doses of 100 mg kg–1 of pumactant and poractant were to RDS among these infants. When used for treatment of RDS, the compared in a multicenter, unmasked trial in 12 NICUs in the use of calfactant resulted in faster weaning of approximately United Kingdom, which enrolled infants between 25 to 29 weeks of the same magnitude as that seen in the comparisons of beractant gestation intubated for presumed RDS.19 The primary outcome for and colfosceril and less pneumothoraces than when colfosceril was this trial was duration of high dependency care (respiratory support given (5.5 versus 10.3%, respectively; RR 0.54, 95% CI 0.35 to 0.84) and oxygen use). About two-thirds of all infants received their with a NNT of 21, but no significant reductions in overall mortality assigned surfactant by 30 min after delivery. The trial was stopped at discharge (9.9 versus 12.0%, respectively) or oxygen use near after approximately 90% of the estimated sample size had been term (5 versus 4%, respectively) were reported. Although no enrolled because of a large difference in mortality among groups, significant differences in total or severe IVH were identified, the but data were reported only for about 200 infants. No difference in incidence of PVL was again higher in the group treated with primary outcome was seen; however, a significant decrease in calfactant (3.3 versus 1.3%, respectively, P ¼ 0.015). Both of these overall mortality among infants receiving poractant was reported studies reported peridosing effects, which were significantly more (14.1% in the poractant group versus 31% in the pumactant group; common among infants given calfactant particularly during repeat RR 0.46, 95% CI 0.26 to 0.80). Also, the occurrence of dosing. pneumothorax was decreased (11.1 versus 22%, respectively; This cumulative experience comparing calfactant, the RR 0.51, 95% CI 0.26 to 0.99), but no difference in use of oxygen animal-derived surfactant with the highest concentration of SP-B, at 36 weeks was shown (46.5 versus 42%, respectively). This is the with colfosceril suggests that most of the clinical benefits favoring only study to ever show a significant difference in overall mortality calfactant relate to acute measures such as more rapid weaning between an animal-derived and a synthetic surfactant. Without and less air leaks, as well as being more effective in preventing these results, the difference in mortality between synthetic and RDS, rather than having a significant impact on overall mortality animal-derived surfactants reported by Soll and Blanco in their or BPD. It remains somewhat a concern that both of these meta-analysis is no longer significant.2 well-designed, masked studies, which included large numbers of Collectively, these data, albeit based on a relatively small infants, showed increases in either severe IVH or PVL associated number of infants, show that poractant, when used at a dose of with the use of calfactant. This question will probably remain 100 mg kg–1, has important clinical advantages only over unresolved since no follow-up data from these trials have pumactant in overall mortality and pneumothorax, but not over ever been reported. colfosceril.

Colfosceril or pumactant versus poractant There have been only two trials comparing colfosceril with New-generation protein-containing synthetic surfactant poractant although one of them did not report respiratory Lucinactant is a new-generation synthetic surfactant that contains outcomes. Thus, the only one contributing data is that of two phospholipids and a high concentration of the synthetic 18 Kukkonen et al., which compared these surfactants for treatment 21-amino-acid hydrophobic peptide sinapultide (KL4 peptide). This

Journal of Perinatology Synthetic surfactants F Moya S26 peptide resembles the hydrophobic–hydrophilic amino-acid pattern approximately 80%. Administration of lucinactant significantly of the tail end of SP-B.8 The concentration of sinapultide in reduced the incidence of RDS compared with colfosceril (OR 0.68, lucinactant is higher than the concentration of SP-B in current 95% CI 0.52 to 0.89), and RDS-related mortality through 14 days of animal-derived products. This surfactant has greater resistance to age was also significantly reduced compared with both colfosceril oxidation and peroxidation than beractant and was shown to (OR 0.43, 95% CI 0.25 to 0.73) and beractant (OR 0.35, 95% CI improve pulmonary function in an animal model of RDS and a 0.18 to 0.66). The incidence of BPD at 36 weeks postmenstrual age pilot study involving preterm infants with established RDS.20–22 (PMA) was lower among those infants receiving lucinactant Lucinactant comes in a solution containing 30 mg of compared with those who got colfosceril (OR 0.75, 95% CI 0.56 to phospholipids per ml for a total recommended dose of 5.8 ml kg–1 0.99), but not beractant. Proportionally, more infants were alive at or 175 mg of phospholipids. It requires warming to 44 1C followed 36 weeks PMA compared with beractant (OR 0.67, 95% CI 0.45 to by vigorous shaking and cooling to body temperature before 1.00, P ¼ 0.05). No difference in pneumothorax or other administration.15 complications of prematurity were reported. Given that this was the To date there have been two multicenter, phase III, first large trial of lucinactant, side effects such as reflux, dose double-blind, randomized, controlled trials examining the efficacy interruption during administration and endotracheal tube of lucinactant in the prevention of RDS.15,23 Inclusion criteria, obstruction were carefully evaluated. These were shown either to approach to surfactant administration and time periods when the occur similarly among groups or to be slightly more common studies were conducted were fairly similar for both trials (Table 2). among infants receiving lucinactant or beractant than colfosceril. The SELECT (Safety and Effectiveness of Lucinactant versus The incidence of these peridosing effects was well within values Exosurf in a Clinical Trial) study compared lucinactant with reported earlier among the few other surfactant comparison trials colfosceril. It was designed as a superiority trial that tested the that have evaluated them.10,16,17 hypothesis of whether the addition of sinapultide to a phospholipid The STAR (Surfaxin in Therapy Against RDS) trial compared mixture conferred any clinical benefit compared with a surfactant lucinactant with poractant.23 In this masked study, which was providing only phospholipids. Beractant was used in the trial as a designed as a non-inferiority trial based on data from the only reference arm. The only published data comparing colfosceril with earlier placebo-controlled trial of poractant, the clinical question beractant for prevention of RDS come from this trial. A total of 50 asked was whether surfactant preparations, one synthetic and one NICUs enrolled 1294 preterm infants between 24 and 32 weeks of animal-derived, when given in similar concentrations of gestational age and between 600 and 1250 g birth weight. These phospholipids but different amounts of SP-B or its mimic, would were randomized to lucinactant, colfosceril and beractant in a result in a clinically meaningful difference in the primary outcome 2:2:1 scheme. The primary outcomes of this study were the of being alive without BPD at 28 days. Twenty-two NICUs enrolled incidence of RDS at 24 h and RDS-related mortality through 124 preterm infants between 600 to 1250 g, which were randomized 14 days of age; these outcomes are essentially similar to those used to receive lucinactant and 128 that received poractant, but data on in the comparison of calfactant with colfosceril.16 These outcomes only 243 infants who received either surfactant within the were adjudicated by an independent, masked committee of predetermined window of 30 min after delivery were reported. The neonatologists and pediatric radiologists. Administration of the upper limit for gestational age in the STAR trial was limited to assigned surfactants was masked and no crossover use of infants younger than 29 weeks. Antenatal steroids were given to surfactants was permitted. Moreover, the trial included ventilatory 85 to 88% of infants enrolled. The study was stopped early after and extubation guidelines. All infants received the initial dose of only about 50% of the estimated sample size had been enrolled, surfactant before 30 min after birth. Antenatal steroid use was primarily because of very slow recruitment. Nonetheless, this is the

Table 2 Summary of the main demographic characteristics of the lucinactant trials

SELECT trial STAR trial

Lucinactant (n ¼ 527) Colfosceril (n ¼ 509) Beractant (n ¼ 258) Lucinactant (n ¼ 124) Poractant (n ¼ 128)

Male, n (%) 263 (49.9) 254 (49.9) 129 (50.0) 60 (48.4) 66 (51.6) Birth weight, g, mean (s.d.) 974 (183) 971 (186) 967 (187) 932 (191) 937 (194) Gestational age, weeks, mean (s.d.) 28.2 (1.9) 28.2 (2.0) 28.1 (2.1) 26.9 (1.2) 27.0 (1.4) Apgar score at 5 mina 7 (3–10) 7 (4–10) 7 (4–10) 8 (3–10) 8 (3–10) Prenatal steroid use, n (%) 415 (79.2) 394 (78.5) 191 (74.3) 109 (87.9) 107 (83.6)

Abbreviations: SELECT, Safety and Effectiveness of Lucinactant versus Exosurf in a Clinical Trial; STAR, Surfaxin in Therapy Against respiratory distress syndrome. aMedian (range).

Journal of Perinatology Synthetic surfactants F Moya S27 second largest comparison study of poractant. The primary decrease respiratory morbidity and mortality in preterm infants outcome of being alive without BPD at 28 days was not with surfactant deficiency. Head-to-head trials have compared significantly different between lucinactant and poractant animal-derived surfactants primarily with the synthetic surfactant (37.8 versus 33.1%, respectively); likewise, there was no difference colfosceril. Only some of these head-to-head comparison trials have in being alive without BPD at 36 weeks (64.7 versus 66.9%, shown differences in important clinical outcomes. Data from these respectively) or in overall mortality at this time point (16 versus studies suggest that the major clinical advantages afforded by the 18.5%, respectively). In addition, no significant differences in other presence of SP-B and SP-C in animal-derived preparations relate to complications of prematurity or in the fraction of inspired oxygen faster onset of action, a reduction in the incidence of RDS when needed during the first 72 h were reported. Moreover, peridosing used prophylactically, and a lower incidence of air leaks and side effects were not different between groups. RDS-related deaths. However, no major benefits in terms of overall mortality or BPD have been shown in these head-to-head One-year outcomes of the lucinactant trials comparisons. A planned follow-up of participating infants out to 1-year corrected Recently, a new-generation synthetic surfactant containing a 24 age from both trials has been reported recently. Given the peptide that mimics SP-B has been evaluated in two clinical trials. similarity of these trials in the populations studied, treatment Findings from these trials15,23 as well as their follow-up study24 approach, end points and contemporary nature, a secondary goal suggest that administration of lucinactant improves short-term defined a priori of this follow-up study was to compare the clinical outcomes compared with colfosceril and results in a outcome of infants receiving lucinactant with the outcome of those survival through 1 year of age that is at least comparable, if not who received other classes of surfactants after combining data from perhaps superior, to that seen with the animal-derived surfactants both trials. In the subsequent follow-up of infants in the SELECT beractant and poractant. This new surfactant and the trials trial, an exceedingly small proportion of infants were lost (<2%), examining its clinical use have not been without criticism.25,26 whereas none of the infants in the STAR trial were lost to However, in a recent statement the American Academy of Pediatrics follow-up. Prespecified rules for the primary analysis in both trials concluded that ‘new synthetic surfactants with surfactant protein stated that infants for whom consent after randomization was like activity are promising new treatments for surfactant-deficiency withdrawn or who were lost to follow-up were counted as deaths. disorders’.27 Future studies using newer approaches to surfactant Nonetheless, survival comparisons on raw data from infants for therapy may be able to further improve the outcome for preterm whom data were available without imputation for death were also infants at risk for or with established RDS. reported. All detailed data are easily accessible in the original publication and are not within the scope of this review. Using Kaplan–Meier survival analysis in the SELECT study, no significant differences were found in the proportion of infants that Disclosure were alive through 1-year corrected age comparing those given F Moya is a paid consultant for Discovery Laboratories but lucinactant, colfosceril or beractant. In the STAR trial, significantly holds no equity. This paper was based on a talk presented at the more infants treated with lucinactant were alive through 1-year Evidence vs Experience in Neonatal Practices Fifth Annual CME corrected age compared with those receiving poractant (P ¼ 0.04). Conference that was supported by an unrestricted educational grant In the combined analysis, survival through 1-year corrected age of from Dey, LP. those infants receiving lucinactant was slightly higher compared with the survival of those who received animal-derived surfactants (P ¼ 0.05). 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